Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof

ABSTRACT

The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis and various spondyloarthritic conditions, including types of axial spondyloarthritis (axSpA)), kits, methods of synthesis, and products-by-process. In various aspects, provided are methods for treating active non-radiographic axSpA (nr-axSpA) and methods for treating active ankylosing spondylitis (AS).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 17/184,194, filed Feb. 24, 2021, which is a continuation ofU.S. patent application Ser. No. 16/656,237, filed Oct. 17, 2019, whichis a continuation of U.S. patent application Ser. No. 15/891,012, filedFeb. 7, 2018, which is a continuation of U.S. patent application Ser.No. 15/295,561, filed Oct. 17, 2016, and which claims the benefit ofU.S. Provisional Application No. 62/242,797, filed Oct. 16, 2015; andclaims the benefit of U.S. Provisional Application No. 62/267,672, filedDec. 15, 2015; and claims the benefit of U.S. Provisional ApplicationNo. 62/301,537, filed Feb. 29, 2016; and claims the benefit of U.S.Provisional Application No. 62/352,380, filed Jun. 20, 2016; all ofwhich are herein incorporated by reference in their entirety. Thisapplication is also a continuation-in-part of U.S. patent applicationSer. No. 17/039,470, filed Sep. 30, 2020, which claims priority to U.S.Provisional Patent Application No. 63/032,042, filed on May 29, 2020;U.S. Provisional Patent Application No. 62/968,849, filed Jan. 31, 2020;U.S. Provisional Patent Application No. 62/927,548, filed Oct. 29, 2019;and U.S. Provisional Patent Application No. 62/908,163, filed Sep. 30,2019, all of which are herein incorporated by reference in theirentirety. This application also claims the benefit of U.S. ProvisionalApplication No. 63/253,109, filed Oct. 6, 2021, which is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to: (a) processes for the preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(referred to herein as “Compound 1”), (b) intermediates used in thepreparation of Compound 1 and processes for preparing the intermediates;(c) solid state forms of Compound 1, (d) pharmaceutical compositionscomprising one or more solid state forms of Compound 1, and, optionally,one or more additional therapeutic agents; (e) methods of treating Januskinase-associated conditions (including rheumatoid arthritis) byadministering one or more solid state forms of Compound 1 to a subjectin need thereof; (f) kits comprising a first pharmaceutical compositioncomprising a solid state form of Compound 1, and, optionally, a secondpharmaceutical composition comprising one or more additional therapeuticagents; (g) methods for the preparation of solid state forms of Compound1; and (h) solid state forms of Compound 1 prepared in accordance withsuch methods.

BACKGROUND OF THE INVENTION

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(“Compound 1”) was first disclosed in International ApplicationWO2011/068881A1, which is herein incorporated by reference in itsentirety. The compound has activity as a Janus kinase (“JAK”) inhibitor,particularly as a JAK-1 inhibitor. Clinical trials are ongoing toevaluate the use of the compound to treat rheumatoid arthritis.

The isolation and commercial-scale preparation of a solid state form ofCompound 1 and corresponding pharmaceutical formulations havingacceptable solid state properties (including chemical stability, thermalstability, solubility, hygroscopicity, and/or particle size), compoundmanufacturability (including yield, impurity rejection duringcrystallization, filtration properties, drying properties, and millingproperties), and formulation feasibility (including stability withrespect to pressure or compression forces during tableting) present anumber of challenges that are discussed in greater detail below.Accordingly, there is a current need for one or more solid state formsof Compound 1 that have an acceptable balance of these properties andcan be used in the preparation of pharmaceutically acceptable soliddosage forms.

Additionally, currently known processes for the preparation of Compound1 involve the use of particularly hazardous reagents, such astrimethylsilyldiazomethane or diazomethane, and do not produce acrystalline product. There is thus also a need for a process forpreparing Compound 1, and pharmaceutically acceptable salts thereof,that avoids the use of particularly hazardous reagents, and can producea crystalline product and crystalline intermediates.

Additionally, sustained peak plasma concentrations can theoretically beachieved by means of sustained release matrix systems. However, whensuch systems are made of hydrophilic polymers, such as HPMC, they seldomprovide pH independent drug release of pH-dependent soluble drugs, andthey are normally incapable of attaining zero-order release except forpractically insoluble drugs. Unexpectedly, is has been discovered thatwhen tartaric acid is used as a pH-modifier in such a system, it allowsCompound 1 to be released at a steady rate regardless of the pH of theenvironment. In an unexpected finding, it was discovered that as atablet containing the hydrophilic polymer matrix system erodes, Compound1 reacts with the HPMC, creating a thicker gel layer which slows therelease of Compound 1 from the tablet. The resulting gel layer providedan environment suitable for Compound 1 to dissolve.

Axial spondyloarthritis (axSpA) encompasses a spectrum of inflammatoryinvolvement of the axial skeleton. Based on the Assessment ofSpondyloArthritis International Society (ASAS) axSpA criteria, thedisease can be further divided into 2 categories by radiographicfindings: ankylosing spondylitis (AS), and an “early” form of axial SpA,referred to as non-radiographic axial spondyloarthritis (nr-axSpA).Patients with nr-axSpA and AS share common epidemiological, genetic, andclinical disease characteristics, including with regard to diseaseactivity, and similar response to treatment. See, e.g., Poddubnyy andSieper, Curr Opin Rheumatol. (2014) 26:377-383.

Per international treatment recommendations, nonsteroidalanti-inflammatory drugs (NSAIDs) are the first-line therapy in axSpA.See, e.g., van der Heijde D et al., Ann Rheum Dis. (2017) 76:978-991;Ward et al., Arthritis Rheumatol. (2016) 68:282-298. After failure oftwo NSAIDs given over a maximum of four weeks, biologicdisease-modifying anti-rheumatic drugs (bDMARDs) are the nextrecommended treatment option. In axSpA, conventional syntheticdisease-modifying anti-rheumatic drugs (csDMARDs) and long-termcorticosteroids are not efficacious and therefore not recommended fortreatment of axial symptoms. See, e.g., van der Heijde D et al., AnnRheum Dis. (2017) 76:978-991. Furthermore, only approximately 45% to 50%of patients show an Assessment of SpondyloArthritis InternationalSociety 40 (ASAS40) response and only approximately 15% to 20% achieve astate of remission in biologic-naïve patients, and response rates areeven less in axSpA patients who had an inadequate response to bDMARDs.See, e.g., Sieper and Poddubnyy, Lancet (2017) 390:73-84; Sieper et al.,Ann Rheum Dis. (2017) 76:571-592; Rudwaleit et al., Arthritis Res Ther.(2010) 12:R117; Deodhar et al., Arthritis Rheumatol. (2019) 71:599-611.To date, other than NSAIDs, there have been no oral targeted therapiesapproved for the treatment of ankylosing spondylitis (AS) ornon-radiographic axSpA.

Psoriatic Arthritis (PsA) is a chronic systemic inflammatory diseaseclassified as a sub-type of spondyloarthritis (SpA) and characterized bythe association of arthritis and psoriasis. The course of PsA is usuallycharacterized by flares and remissions. Left untreated, patients withPsA can have persistent inflammation, progressive joint damage,disability, and a reduced life expectancy. Initial treatment of themusculoskeletal symptoms is composed of nonsteroidal anti-inflammatorydrugs (NSAIDs) and local corticosteroid injections, while topicaltherapies are used for the initial treatment of psoriasis. For subjectswho experience lack of efficacy or toxicity with these measures,systemic therapy with non-biologic disease modifying anti-rheumaticdrugs (non-biologic DMARDs) (e.g., methotrexate [MTX], leflunomide[LEF], sulfasalazine [SSZ]) and ciclosporin A, followed by anti-tumornecrosis factor (TNF) therapy in subjects who do not respond adequately,is recommended. Other biologic therapies (e.g., IL-12/23 or IL-17inhibitors) are also recommended as alternatives to anti-TNF inhibitorsin selected PsA subjects. See, e.g., Gossec et al., Ann Rheum Dis.(2016) 75:499-510; Coates et al., Arthritis Rheumatol. (2016)68:1060-71. However, despite the beneficial results achieved withcurrently available biologic agents, approximately 40% of patients donot have at least 20% improvement in American College of Rheumatology(ACR) scores and only 58% to 61% of patients with PsA who receive themare able to achieve clinical remission after 1 year of treatment, withonly approximately 43% achieving sustained remission for at least 1year. See, e.g., Gossec et al., Ann Rheum Dis. (2016) 75:499-510;Alamanos et al., J Rheumatol. (2003) 30:2641-2644; Savolainen et al., JRheumatol. (2003) 30:2460-8; Sandborn, Dig Dis. (2010) 28:536-42; Saberet al., Arthritis Res Therapy (2010) 12: R94; Perrotta et al., JRheumatol. (2016) 43:350-5.

Thus, there continues to remain a clear medical need for additionaltherapeutic options for the treatment of non-radiographic axialspondyloarthritis (nr-axSpA), ankylosing spondylitis (AS), psoriaticarthritis (PsA), and psoriasis (PsO), including PsO as a skinmanifestation of PsA.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure relates to pharmaceuticalcompositions comprising one or more solid state forms of Compound 1,and, optionally, one or more additional therapeutic agents.

In another aspect, the present disclosure relates to methods for thepreparation of a solid state form of Compound 1.

In another aspect, the present disclosure relates to solid state formsof Compound 1 prepared in accordance with such methods.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 7.5 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 15 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 30 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 45 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure is directed to an extendedrelease formulation for oral administration comprising Compound 1 or apharmaceutically acceptable salt thereof, a hydrophilic polymer, and apH modifier, wherein the hydrophilic polymer, in contact with water,forms a gel layer that provides an environment suitable for Compound 1and the pH modifier to dissolve.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a therapeutically effective amount of asolid state form of Compound 1. In another aspect, the disclosurerelates to a pharmaceutical composition comprising a therapeuticallyeffective amount of a solid state form of Compound 1 as described in thepresent disclosure, for use in treatment of a JAK-associated condition(such as rheumatoid arthritis) in a subject, particularly in a humansubject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatingrheumatoid arthritis, wherein the term “rheumatoid arthritis” includesjuvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosingspondylitis disease, Sjogren's syndrome, psoriatic arthritis.

In another aspect, the present disclosure relates to methods of treatinginflammatory bowel disease, wherein the term “inflammatory boweldisease” includes Crohn's disease, pediatric Crohn's disease andulcerative colitis.

In another aspect, the present disclosure relates to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis and systemic lupus erythematosus in ahuman subject suffering from or susceptible to such a condition, themethod comprising administering to the subject a therapeuticallyeffective amount a solid state form of Compound 1. In another aspect,the disclosure relates to a pharmaceutical composition comprising atherapeutically effective amount of a solid state form of Compound 1 asdescribed in the present disclosure, for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a solid state form of Compound 1, incombination with one or more additional therapeutic agents (e.g., atherapeutic agent for treating rheumatoid arthritis that is not a JAKinhibitor). In another aspect, the disclosure relates to apharmaceutical composition comprising a solid state form of Compound 1,as described in the present disclosure, in combination with one or moreadditional therapeutic agents (e.g., a therapeutic agent for treatingrheumatoid arthritis that is not a JAK inhibitor), for use in treatmentof a JAK-associated condition (such as rheumatoid arthritis) in asubject, particularly in a human subject suffering from or susceptibleto the condition.

In another aspect, the present disclosure relates to a method oftreating active non-radiographic axial spondyloarthritis in a subject inneed thereof, the method comprising orally administering to the subjectonce a day for at least 14 weeks a dose of upadacitinib freebase, or apharmaceutically acceptable salt thereof, in an amount sufficient todeliver 15 mg of upadacitinib freebase equivalent, wherein the subjectachieves an ASAS40 response within 14 weeks of administration of thefirst dose. In some embodiments, the subject fulfills at baseline the2009 ASAS classification criteria for axial spondyloarthritis, but doesnot meet the radiologic criteria of the 1984 modified New York criteriafor ankylosing spondylitis. In some embodiments, the subject meets thefollowing criteria at screening and baseline: a) Bath AnkylosingSpondylitis Disease Activity Index (BASDAI) score of ≥4; b) a Patient'sAssessment of Total Back Pain (Total Back Pain score) of ≥4 based on a0-10 numerical rating scale; and c) an objective sign of inflammatoryactivity selected from the group consisting of: i. an objective sign ofactive inflammation on MRI of sacroiliac (SI) joints, and ii.high-sensitivity C reactive protein>upper limit of normal (ULN). In someembodiments, the subject is bDMARD naïve at baseline. In someembodiments, the subject has had an inadequate response or intoleranceto a bDMARD at baseline. In some embodiments, prior to administration ofthe first dose, the subject has been administered one bDMARD, anddiscontinued use of the bDMARD due to intolerance or lack of efficacy atbaseline. In some embodiments, the bDMARD is a tumor necrosis factor(TNF) inhibitor or an interleukin (IL)-17 inhibitor. In someembodiments, the subject has had an inadequate response or intoleranceto at least 2 NSAIDs, has an intolerance to NSAIDS, and/or has acontraindication for NSAIDs at baseline. In some embodiments, thesubject achieves within 14 weeks of administration of the first dose atleast one additional result selected from the group consisting of:improvement from baseline in Ankylosing Spondylitis Disease ActivityScore (ASDAS); improvement from baseline in magnetic resonance imaging(MRI) Spondyloarthritis Research Consortium of Canada (SPARCC) score forSI joints (MRI-SI joints SPARCC); BASDAI 50 response; ASDAS (CRP)Inactive Disease (ID); Improvement from baseline in Total Back Pain;Improvement from baseline in Nocturnal Back Pain; ASDAS (CRP) LowDisease Activity; ASAS partial remission (PR); improvement from baselinein Bath Ankylosing Spondylitis Functional Index (BASFI); improvementfrom baseline in Ankylosing Spondylitis Quality of Life (ASQoL);improvement from baseline in ASAS Health Index (HI); ASAS20 response;improvement from baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES); and improvement from baseline in Linear BathAnkylosing Spondylitis Metrology Index (BASMI_(lin)).

In another aspect, the present disclosure relates to a method oftreating active ankylosing spondylitis in a subject in need thereof, themethod comprising orally administering to the subject once a day for atleast 14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves anAssessment of SpondyloArthritis International Society 40 (ASAS40)response within 14 weeks of administration of the first dose, andwherein the subject has had an inadequate response or intolerance to abiologic disease-modifying anti-rheumatic drug (bDMARD) at baseline. Insome embodiments, the method is used to treat a population of subjects,at least 10% of the subjects in the treated population achieve an ASAS40response within 14 weeks of administration of the first dose, whereinthe subjects in the treated population have had an inadequate responseor intolerance to a biologic disease-modifying anti-rheumatic drug(bDMARD) at baseline. In some embodiments, the subject or subjects inthe treated population further achieve within 14 weeks of administrationof the first dose at least one result selected from the group consistingof: improvement from baseline in Ankylosing Spondylitis Disease ActivityScore (ASDAS) (CRP); improvement from baseline in magnetic resonanceimaging (MRI) Spondyloarthritis Research Consortium of Canada (SPARCC)score for spine (MRI-Spine SPARCC); Bath Ankylosing Spondylitis DiseaseActivity Index 50 (BASDAI50) response; ASAS20 response; ASDAS inactivedisease (ID); Improvement from baseline in Patient's Assessment of TotalBack Pain (Total Back Pain score); Improvement from baseline inPatient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain); ASDAS(CRP) Low Diseases Activity (LDA); Improvement from baseline in BathAnkylosing Spondylitis Functional Index (BASFI) (Function); ASAS partialremission (PR); Improvement from baseline in Ankylosing SpondylitisQuality of Life (ASQoL); Improvement from baseline in ASAS Health Index(HI); Improvement from baseline in Linear Bath Ankylosing SpondylitisMetrology Index (BASMIlin) (Mobility); and improvement from baseline inMaastricht Ankylosing Spondylitis Enthesitis Score (MASES) (Enthesitis).In some embodiments, the subject or subjects in the treated populationfurther achieve within 14 weeks of administration of the first dose eachresult. In some embodiments, the subject or subjects in the treatedpopulation fulfill the 1984 modified New York Criteria for ankylosingspondylitis at baseline. In some embodiments, the subject or subjects inthe treated population meet the following criteria: a Bath AnkylosingSpondylitis Disease Activity Index (BASDAI) score ≥4; and a Patient'sAssessment of Total Back Pain (Total Back Pain score) of ≥4 based on a0-10 numerical rating scale. In some embodiments, the subject orsubjects in the treated population have had an inadequate response orintolerance to a biologic disease-modifying anti-rheumatic drug (bDMARD)at baseline. In some embodiments, prior to administration of the firstdose, the subject or subjects in the treated population have beenadministered one bDMARD, and discontinued use of the bDMARD due tointolerance or lack of efficacy at baseline. In some embodiments, thebDMARD is a tumor necrosis factor (TNF) inhibitor or an interleukin(IL)-17 inhibitor. In some embodiments, the subject or subjects in thetreated population have had an inadequate response or intolerance to atleast two NSAIDs, intolerance to NSAIDS, and/or contraindication forNSAIDs at baseline.

In another aspect, the present disclosure relates to kits comprising oneor more pharmaceutical compositions comprising a solid state form ofCompound 1. The kit optionally can comprise another pharmaceuticalcomposition comprising one or more additional therapeutic agents and/orinstructions, for example, instructions for using the kit.

The below recited Embodiments 1-25 set forth certain aspects of themethods as described herein.

Embodiment 1: In certain aspects, provided is a method of treatingactive ankylosing spondylitis (AS) in a subject in need thereof, themethod comprising orally administering to the subject once a day for atleast 14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves anAssessment of SpondyloArthritis International Society 40 (ASAS40)response within 14 weeks of administration of the first dose.

Embodiment 2: The method of Embodiment 1, wherein when the method isused to treat a population of subjects, at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 44%, or at least 45% of the subjects in the treated populationachieve an ASAS40 response within 14 weeks of administration of thefirst dose. In certain embodiments of the method of Embodiment 1,wherein when the method is used to treat a population of subjects, astatistically significant population of the subjects in the treatedpopulation achieves an ASAS40 response within 14 weeks of administrationof the first dose.

Embodiment 3: The method of Embodiment 1 or 2, wherein the subject orsubjects in the treated population suffering from active AS at baselinefurther achieve within 14 weeks of administration of the first dose atleast one result selected from the group consisting of:

-   -   a. improvement from baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS) (CRP);    -   b. improvement from baseline in magnetic resonance imaging (MRI)        Spondyloarthritis Research Consortium of Canada (SPARCC) score        for spine (MRI-Spine SPARCC);    -   c. Bath Ankylosing Spondylitis Disease Activity Index 50        (BASDAI50) response;    -   d. ASAS20 response;    -   e. ASDAS (CRP) Inactive Disease (ASDAS score <1.3);    -   f. Improvement from baseline in Patient's Assessment of Total        Back Pain (Total Back Pain score);    -   g. Improvement from baseline in Patient's Assessment of        Nocturnal Back Pain (Nocturnal Back Pain);    -   h. ASDAS low disease activity (LDA);    -   i. improvement from baseline in Bath Ankylosing Spondylitis        Functional Index (BASFI);    -   j. ASAS partial remission (PR);    -   k. Improvement from baseline in Ankylosing Spondylitis Quality        of Life (ASQoL);    -   l. improvement from baseline in ASAS Health Indes (HI);    -   m. improvement from baseline in Linear Bath Ankylosing        Spondylitis Metrology Index (BASMI_(lin)); and    -   n. Improvement from baseline in Maastricht Ankylosing        Spondylitis Enthesitis Score (MASES) (Enthesitis).

In certain embodiments of the method of Embodiment 1 or 2, when themethod is used to treat a population of subjects, at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 44%, or at least 45% of the subjects in the treatedpopulation achieve at least one of these results within 14 weeks ofadministration of the first dose. In other embodiments of the method ofEmbodiment 1 or 2, when the method is used to treat a population ofsubjects, a statistically significant population of subjects in thetreated population achieves at least one result within 14 weeks ofadministration of the first dose.

Embodiment 4: The method of Embodiment 3, wherein the subject orsubjects in the treated population suffering from active AS at baselinefurther achieve within 14 weeks of administration of the first dose eachresult.

Embodiment 5: The method of any one of Embodiments 1-4, wherein thesubject or subjects in the treated population fulfill the 1984 modifiedNew York Criteria for ankylosing spondylitis at baseline.

Embodiment 6: The method of any one of Embodiments 1-5, wherein thesubject or subjects in the treated population meet the followingcriteria at screening and baseline:

-   -   a. a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score ≥4; and    -   b. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale.

Embodiment 7: The method of any one of Embodiments 1-6, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a biologic disease-modifying anti-rheumaticdrug (bDMARD) at baseline.

Embodiment 8: The method of Embodiment 7, wherein prior toadministration of the first dose, the subject or subjects in the treatedpopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 9: The method of Embodiment 8, wherein the bDMARD is a tumornecrosis factor (TNF) inhibitor or an interleukin (IL)-17 inhibitor.

Embodiment 10: The method of any one of Embodiments 1-9, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to at least two NSAIDs, intolerance to NSAIDS,and/or contraindication for NSAIDs at baseline.

Embodiment 11: In other aspects, provided is a method of treating activenon-radiographic axial spondyloarthritis in a subject in need thereof,the method comprising orally administering to the subject once a day forat least 14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves an ASAS40response within 14 weeks of administration of the first dose. In certainembodiments, when the method is used to treat a population of subjects,at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 44%, or at least 45% of the subjectsin the treated population achieve an ASAS40 response within 14 weeks ofadministration of the first dose. In certain embodiments, astatistically significant population of subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose.

Embodiment 12: The method of Embodiment 11, wherein the subject orsubjects in the treated population fulfill at baseline the 2009 ASASclassification criteria for axial spondyloarthritis, but does not meetthe radiologic criteria of the 1984 modified New York criteria forankylosing spondylitis.

Embodiment 13: The method of Embodiment 11, wherein the subject orsubjects in the treated population meet the following criteria atscreening and baseline:

-   -   a. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score of ≥4;    -   b. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale; and    -   c. an objective sign of inflammatory activity selected from the        group consisting of:        -   i. an objective sign of active inflammation on MRI of            sacroiliac (SI) joints, and        -   ii. high-sensitivity C reactive protein>upper limit of            normal (ULN).

Embodiment 14: The method of any one of Embodiments 11-13, wherein thesubject or subjects in the treated population are bDMARD naïve atbaseline.

Embodiment 15: The method of any one of Embodiments 11-13, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a bDMARD at baseline.

Embodiment 16: The method of Embodiment 15, wherein prior toadministration of the first dose, the subject or subjects in the treatedpopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 17: The method of Embodiment 16, wherein the bDMARD is atumor necrosis factor (TNF) inhibitor or an interleukin (IL)-17inhibitor.

Embodiment 18: The method of any one of Embodiments 11-17, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to at least 2 NSAIDs, has an intolerance toNSAIDS, and/or has a contraindication for NSAIDs at baseline.

Embodiment 19: The method of any one of Embodiments 11-18, wherein thesubject or subjects in the treated population achieve within 14 weeks ofadministration of the first dose at least one additional result selectedfrom the group consisting of:

-   -   a. improvement from baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS) (CRP);    -   b. improvement from baseline in magnetic resonance imaging (MRI)        Spondyloarthritis Research Consortium of Canada (SPARCC) score        for SI joints (MRI-SI joints SPARCC);    -   c. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        50 response;    -   d. ASDAS (CRP) Inactive Disease (ASDAS score <1.3);    -   e. improvement from baseline in Total Back Pain;    -   f. improvement from baseline in Nocturnal Back Pain;    -   g. ASDAS Low Disease (ASDAS score <2.1);    -   h. ASAS partial remission (PR);    -   i. improvement from baseline in Bath Ankylosing Spondylitis        Functional Index (BASFI);    -   j. improvement from baseline in Ankylosing Spondylitis Quality        of Life (ASQoL);    -   k. improvement from baseline in ASAS Health Index (HI);    -   l. ASAS20 response;    -   m. improvement from baseline in Linear Bath Ankylosing        Spondylitis Metrology Index (BASMI_(lin)) and    -   n. improvement from baseline in Maastricht Ankylosing        Spondylitis Enthesitis Score (MASES).

In certain embodiments of the method of any one of Embodiments 11-18,wherein when the method is used to treat a population of subjects, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 44%, or at least 45% of the subjectsin the treated population achieve at least one result within 14 weeks ofadministration of the first dose. In certain embodiments of the methodof any one of Embodiments 11-18, wherein when the method is used totreat a population of subjects, a statistically significant populationof subjects in the treated population achieves at least one resultwithin 14 weeks of administration of the first dose.

Embodiment 20: The method of any one of Embodiments 1-19, wherein thesubject is an adult subject, or the subjects in the treated populationare adult subjects.

Embodiment 21: The method of any one of Embodiments 1-19, wherein theASAS40 response is maintained or improved after Week 14 by continuing toadminister the daily dose. In one aspect, the ASAS40 response ismaintained or improved up to and including Week 104 or up to andincluding Week 152.

Embodiment 22: The method of any one of Embodiments 1-10, wherein thesubject or subjects in the treated population further achieve ASAS40within 4 weeks of administration of the first dose.

Embodiment 23: The method of any one of Embodiments 1-10, wherein thesubject or subjects in the treated population further achieved ASAS40within 4 weeks of administration of the first dose, and wherein theASAS40 is maintained or improved after Week 14 by continuing toadminister the daily dose.

Embodiment 24: The method of any one of Embodiments 11-19, wherein thesubject or subjects in the treated population further achieve ASAS40within 2 weeks of administration of the first dose.

Embodiment 25: The method of any one of Embodiments 11-19, wherein thesubject or subjects in the treated population further achieved ASAS40within 2 weeks of administration of the first dose, and wherein theASAS40 is maintained or improved after Week 14 by continuing toadminister the daily dose.

Embodiment 26: In another aspect, provided is a method of treatingactive ankylosing spondylitis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves ASASpartial remission (PR), ASDAS low disease activity (LDA), ASDAS inactivedisease (ID), ASDAS major improvement (MI), and/or ASDAS clinicallyimportant improvement (CII) within 14 weeks of administration of thefirst dose.

Embodiment 27: The method of Embodiment 26, wherein when the method isused to treat a population of subjects, a portion of the subjects in thetreated population achieve ASAS partial remission (PR), ASDAS lowdisease activity (LDA), ASDAS inactive disease (ID), ASDAS majorimprovement (MI), and/or ASDAS clinically important improvement (CII)within 14 weeks of administration of the first dose. In certainembodiments of Embodiment 50, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population achieve ASAS partial remission(PR), ASDAS low disease activity (LDA), ASDAS inactive disease (ID),ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) within 14 weeks of administration of the first dose.In certain embodiments of Embodiment 50, a statistically significantpopulation of subjects in the treated population achieves ASAS partialremission (PR), ASDAS low disease activity (LDA), ASDAS inactive disease(ID), ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) within 14 weeks of administration of the first dose.

Embodiment 28: The method of Embodiment 26 or 27, wherein the subject orsubjects in the treated population further achieve within 14 weeks ofadministration of the first dose each result.

Embodiment 29: The method of any one of Embodiments 26-28, wherein thesubject or subjects in the treated population fulfill the 1984 modifiedNew York Criteria for ankylosing spondylitis at baseline.

Embodiment 30: The method of any one of Embodiments 26-28, wherein thesubject or subjects in the treated population fulfill the 2009 ASASclassification criteria at baseline.

Embodiment 31: The method of any one of Embodiments 26-30, wherein thesubject or subjects in the treated population meet at least one criteriaat baseline selected from the group consisting of:

-   -   a. a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score ≥4;    -   b. an Ankylosing Spondylitis Disease Activity Score (ASDAS) of        ≥2.1; and    -   c. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale.

Embodiment 32: The method of any one of Embodiments 26-31, wherein thesubject or subjects in the treated population are biologicdisease-modifying anti-rheumatic drug (bDMARD) naïve at baseline.

Embodiment 33: The method of any one of Embodiments 26-32, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a biologic disease-modifying anti-rheumaticdrug (bDMARD) at baseline.

Embodiment 34: The method of Embodiments 33, wherein prior toadministration of the first dose, the subject or subjects in thepopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 35: The method of Embodiments 34, wherein the bDMARD is atumor necrosis factor (TNF) inhibitor or an interleukin (IL)-17inhibitor.

Embodiment 36: The method of any one of Embodiments 26-32, wherein thesubject or subjects in the population have had an inadequate response orintolerance to at least two NSAIDs, intolerance to NSAIDS, and/orcontraindication for NSAIDs at baseline.

Embodiment 37: The method of any one of Embodiments 26-36, wherein theASAS partial remission (PR), ASDAS low disease activity (LDA), ASDASinactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) is maintained or improved afterWeek 14 by continuing to administer the daily dose.

Embodiment 38: The method of any one of Embodiments 26-37, wherein thesubject or subjects in the treated population further achieve ASASpartial remission (PR), ASDAS low disease activity (LDA), ASDAS inactivedisease (ID), ASDAS major improvement (MI), and/or ASDAS clinicallyimportant improvement (CII) within 2 weeks of administration of thefirst dose. In certain embodiments of Embodiment 61, a statisticallysignificant population of subjects in the treated population achieveASAS partial remission (PR), ASDAS low disease activity (LDA), ASDASinactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) within 2 weeks of administrationof the first dose. In certain embodiments of Embodiment 61, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve ASAS partial remission (PR), ASDAS low diseaseactivity (LDA), ASDAS inactive disease (ID), ASDAS major improvement(MI), and/or ASDAS clinically important improvement (CII) within 2 weeksof administration of the first dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1)clinical study plan. Asterisk (*) indicates radiographs were conductedduring the screening period. ASAS40=Assessment of SpondyloArthritisinternational Society 40% response. MRI=magnetic resonance imaging.QD=once daily. SI=sacroiliac.

FIG. 2 depicts the multiplicity-controlled analysis used in the Phase2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial using theHochberg Procedure. Asterisk (*) indicates result was statisticallysignificant in multiplicity-controlled analysis, otherwise nominal pvalues are shown. The multiplicity-controlled endpoints are tested in asequential manner with initially assigned a=0.05. Statisticalsignificance (p<0.05) can be claimed for a lower ranked endpoint only ifthe previous endpoint in the sequence meets the requirements ofstatistical significance. ASAS HI can be evaluated only if the group ofendpoints tested by Hochberg procedure are all statisticallysignificant. Within the Hochberg procedure, BASDAI50, BASFI, and ASAS PRachieved the required statistical significance; however, WPAI, MASES,BASMI, and ASQoL did not meet the requirement of statisticalsignificance, so ASAS HI was not tested. Per Hochberg procedure, allendpoints are tested using assigned a according to the magnitude ofnominal p value starting from the largest one. If an endpoint isrejected, all endpoints with smaller p values are rejected. If anendpoint fails, then the procedure advances to the next endpoint.ASAS=Assessment of SpondyloArthritis International Society. ASAS40=ASAS40% response. ASAS HI=ASAS Health Index. ASAS PR=ASAS Partial Remission.ASDAS=Ankylosing Spondylitis Disease Activity Score. ASQoL=AnkylosingSpondylitis Quality of Life. BASDAI50=50% improvement from baseline inBath Ankylosing Spondylitis Disease Activity Index. BASFI=BathAnkylosing Spondylitis Functional Index. BASMI=Bath AnkylosingSpondylitis Metrology Index. MASES=Maastricht Ankylosing SpondylitisEnthesitis Score. MRI=magnetic resonance imaging. QD=once daily.SPARCC=Spondyloarthritis Research Consortium of Canada. WPAI=WorkProductivity and Activity Impairment.

FIGS. 3A-3C and FIGS. 3D-3N, respectively depict the Week 14 results ofthe Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial forkey clinical efficacy endpoints, and time course of key endpoints up toand including Week 64. FIG. 3A depicts the ASAS20, ASAS40, ASAS PR, andBASDAI50 Responses at Week 14; FIG. 3B depicts the change from Baselinein SPARCC MRI Spine and SI Joint Scores at Week 14; and FIG. 3C depictsother Multiplicity-Controlled Key Secondary Efficacy Endpoints at Week14. The results demonstrate the study met its primary endpoint, withstatistically significantly more patients treated with upadacitinibfreebase versus placebo achieving ASAS40 response at Week 14 (48/93[51.6%] vs 24/94 [25.5%]; p=0.0003) with a treatment difference (95% CI)of 26.1% (12.6-39.5%). All endpoints were multiplicity controlled,except for ASAS20 and SPARCC MRI SI joint. The multiplicity-controlledsecondary endpoints were tested in a sequential manner: ASDAS, SPARCCMRI Spine, group of endpoints tested by Hochberg procedure (BASDAI50,ASQoL, ASAS PR, BASFI, BASMI, MASES, and WPAI), and ASAS HI. For FIGS.12L-12N, Asterisk (***) indicates P<0.001, Asterisk (**) P<0.01; andAsterisk (*) P<0.05. For other Figures, Asterisk (*) indicatesstatistically significant in multiplicity-controlled analysis, otherwisenominal p values are shown. Accounting for multiplicity adjustment,change from baseline to Week 14 in ASDAS (FIG. 12C), SPARCC MRI spine(FIG. 3B), and BASFI (FIG. 3C) and proportion of patients who achievedBASDAI50 (FIG. 3A) and ASAS PR (FIG. 12A) were statistically significantfor upadacitinib freebase versus placebo. FIGS. 3D-3K depict the timecourse of the ASAS40 (FIG. 12D), ASAS20 (FIG. 3E), ASAS partialremission (PR) (FIG. 3F), BASDAI50 Responses (FIG. 3G), ASDAS inactivedisease (ID) (FIG. 3H), ASDAS low disease activity (LDA) (FIG. 3I),ASDAS major improvement (MI) (FIG. 3J), and ASDAS clinically importantimprovement (CII) (FIG. 3K) up to and including Week 64. At week 14, theplacebo group was rescued and administered 15 mg upadacitinib free base(Placebo→Upadacitinib 15 mg QD). Patients who switched from placebo toupadacitinib at week 14 showed a similar efficacy response compared withthose who received continuous upadacitinib free base from Day 0. Thedata suggests upadacitinib 15 mg QD, showing achievement of efficacy atWeek 14, and sustaining or even improving upon this efficacy up to andincluding Week 64, will help to address an unmet need for patients withAS (as well as in patients with non-radiographic axial spondyloarthritis(nr-axSpA)), especially in those patients who have active disease andhave inadequately responded to NSAIDs. A significantly higher proportionof patients receiving upadacitinib versus placebo achieved ≥30% (FIG.3L) and ≥50% reduction (FIG. 3M) in Patient's Global Assessment of pain(PtPain) as early as week 2, and ≥70% reduction (FIG. 3N) as early asweek 4, and efficacy achieved was sustained thereafter. Patients whoswitched from placebo to open-label upadacitinib at week 14 generallyreached the same level of pain reduction after week 14 as thoseinitially randomized to upadacitinib. MASES assessment includes patientswith baseline enthesitis; WPAI assessment includes patients currentlyemployed; SPARCC MRI assessment population as pre-specified in thestatistical analysis plan (baseline included MRI data ≤3 days afterfirst dose of study drug, and Week 14 included MRI data up to first doseof Period 2 study drug). ASAS20=Assessment of SpondyloArthritisinternational Society 20 response. ASAS40=Assessment ofSpondyloArthritis international Society 40 response. ASQoL=AnkylosingSpondylitis Quality of Life score. ASDAS=Ankylosing Spondylitis DiseaseActivity Score. BASDAI50=50% improvement from baseline in BathAnkylosing Spondylitis Disease Activity Index. BASFI=Bath AnkylosingSpondylitis Functional Index. BASMI=Bath Ankylosing SpondylitisMetrology Index. HI=Health Index. MASES=Maastricht AnkylosingSpondylitis Enthesitis Score. MRI=magnetic resonance imaging. MMRM=mixedmodel for repeated measures. NRI=non-responder imputation. AO=AsObserved. PR=partial remission. QD=once daily. SI, sacroiliac.SPARCC=Spondyloarthritis Research Consortium of Canada. WPAI=WorkProductivity and Activity Impairment.

FIGS. 4A-4E depict data for ASAS domains (ASAS40, PtGA, Back Pain,BASFI, and Inflammation) measured at Weeks 2, 4, 8, 12, and 14 in thePhase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial. Asignificant difference for upadacitinib freebase versus placebo inASAS40 (FIG. 4A) and the mean change for each of its four individualdomains (FIGS. 4B-4E) was observed as early as the first post-baselinevisit (Week 2), and this difference was maintained consistently throughWeek 14, with Week 14 achieving a statistically significant differencein multiplicity-controlled analysis. Back pain defined on a numericalrating scale (0-10) based on the following question, “What is the amountof back pain that you experienced at any time during the last week?Inflammation is defined as mean of Questions 5 and 6 of the BASDAI.BASDAI=Bath Ankylosing Spondylitis Disease Activity Index. BASFI=BathAnkylosing Spondylitis Functional Index. BL=baseline. LSM=least squaresmean. MMRM=mixed model for repeated measures. NRI=non-responderimputation. PtGA=Patient Global Assessment of disease activity. QD=oncedaily.

FIG. 5 depicts the pre-specified and supplemental SPARCC MRI Analysis ofthe Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial. TheSPARCC MRI assessment population was pre-specified in the statisticalanalysis plan (baseline included MRI data ≤3 days after first dose ofstudy drug, and Week 14 included MRI data up to first dose of period 2study drug). The supplemental SPARCC MRI analysis included all MRI datacollected at nominal visits at baseline and Week 14, and confirmed theresults of the primary SPARCC MRI analysis for both the spine and SIjoints. MMRM=mixed model for repeated measures. MRI=magnetic resonanceimaging. QD=once daily. SI=sacroiliac. SPARCC=Spondyloarthritis ResearchConsortium of Canada.

FIGS. 6A-6D depict the cumulative probability plots of change in SPARCCscores as described in FIG. 5 for the Phase 2/3 Ankylosing Spondylitis(SELECT-AXIS 1), demonstrating that the SPARCC MRI spine and SI jointscores improved from baseline to week 14 to a greater extent in patientsreceiving upadacitinib compared with placebo. Results for the primaryMRI analyses (FIGS. 6A-6B) and supplemental MRI analyses (FIGS. 6C-6D)were consistent.

FIGS. 7A-7C depict the percentage of patients achieving ASDAS LDA, ASDASID, ASDAS CII, and ASDAS MI at Week 14 (FIG. 7A), Change From Baselinein Mean ASDAS Over Time (FIG. 7B), and ASDAS MI Over Time (FIG. 7C) inthe Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial. Theproportions of patients who achieved ASDAS LDA, ASDAS ID, ASDAS CII, andASDAS MI were greater (nominal p<0.0001) for upadacitinib freebaseversus placebo at Week 14 (FIG. 7A). ASDAS=Ankylosing SpondylitisDisease Activity Score. BL=baseline. CII=Clinically ImportantImprovement (≥1.1-point decrease from baseline). ID=Inactive Disease(score <1.3). LDA=low disease activity (<2.1). MI=Major Improvement(≥2-point decrease from baseline). MMRM=mixed model for repeatedmeasures. NRI=non-responder imputation. QD=once daily.

FIGS. 8A-8D depict the least squares mean (LSM) change from baseline inindividual ASDAS components over time in the Phase 2/3 AnkylosingSpondylitis (SELECT-AXIS 1) clinical trial. Improvement in the meanASDAS (FIG. 8B) and the individual ASDAS components (FIGS. 8A-17D) wasseen as early as Week 2 with continued improvement up to Week 14 withupadacitinib freebase. Spinal pain=BASDAI Question 2. Peripheralpain/swelling=BASDAI Question 3. Duration of morning stiffness=BASDAIQuestion 6. ASDAS=Ankylosing Spondylitis Disease Activity Score.BASDAI=Bath Ankylosing Spondylitis Disease Activity Index. BL=baseline.hsCRP=high-sensitivity C-reactive protein. MMRM=mixed model for repeatedmeasures. PtGA=Patient Global Assessment of disease activity. QD=oncedaily.

FIG. 9 depicts the Phase 3 study design for the treatment of AS andnr-AxSpA subjects. AS=ankylosing spondylitis; ASAS=Assessment ofSpondyloArthritis International Society; bDMARD-IR=biologicdisease-modifying anti-rheumatic drug inadequate responder;nr-axSpA=non-radiographic axial spondyloarthritis; DB=double blind;PBO=placebo; QD=once daily; UPA=upadacitinib freebase.

FIGS. 10A-10B depict the Week 14 results of the Phase 3 AnkylosingSpondylitis (SELECT AXIS-2) clinical trial for the primary endpointASAS40 response in bDMARD-IR subjects. FIG. 2A depicts ASAS40 responsefor placebo vs. upadacitinib freebase 15 mg QD at Week 14; FIG. 2Bdepicts the ASAS40 response rate for placebo vs. upadacitinib freebase15 mg QD over time (Baseline to Week 14). The results demonstrate thestudy met the primary endpoint. Upadacitinib showed onset of effect inASAS40 as early as Week 4. ASAS40=Assessment of SpondyloArthritisInternational Society 40 Response; QD=once daily; PBO=placebo;UPA=upadacitinib freebase; *=significant after multiplicity adjustment.

FIGS. 11A-11F depict the Week 14 results of the Phase 3 AnkylosingSpondylitis (SELECT AXIS-2) clinical trial for key clinical efficacyendpoints for placebo vs 15 mg upadacitinib freebase once daily. FIG.11A depicts the ASAS20, ASAS40, ASAS PR, and BASDAI50 responses at Week14; FIG. 11B depicts the ASDAS Inactive Disease and ASDAS Low DiseaseActivity responses at Week 14; FIG. 11C depicts the ASDAS (CRP), TotalBack Pain, Nocturnal Back Pain, and BASFI responses at Week 14; FIG. 11Ddepicts the MRI SPARCC Spine score and the MRI SPARCC Sacroliac JointScore at Week 14; FIG. 11E depicts the ASQoL and ASAS Health Indexscores at Week 14; and FIG. 11F depicts the BASMI and MASES scores atWeek 14. PBO=placebo; UPA=upadacitinib freebase; ASDAS=AnkylosingSpondylitis Disease Activity Score; BASDAI50=50% improvement frombaseline in Bath Ankylosing Spondylitis Disease Activity Index;BASFI=Bath Ankylosing Spondylitis Functional Index; MRI=magneticresonance imaging; SPARCC=Spondyloarthritis Research Consortium ofCanada; ASQoL=Ankylosing Spondylitis Quality of Life score;ASAS=Assessment of SpondyloArthritis International Society; BASMI=BathAnkylosing Spondylitis Metrology Index; MASES=Maastricht AnkylosingSpondylitis Enthesitis Score; BL=Baseline; *=significant aftermultiplicity-adjustment.

FIG. 12 depicts the response rate for placebo and upadacitinib freebasein bDMARD-naïve (SELECT AXIS-1; US Pat App No. 2021/0228575) andbDMARD-IR (SELECT AXIS-2, Study 1) studies at Week 14 for ASAS20,ASAS40, ASASPR; ASDAS LDA; ASDAS ID; and BASDAI50. PBO=placebo;UPA=upadacitinib; ASAS=Assessment of SpondyloArthritis InternationalSociety; ASASPR=Assessment of SpondyloArthritis International SocietyPartial Remission; ASDAS=Ankylosing Spondylitis Disease Activity Score;LDA=Low Disease Activity; ID=Inactive Disease; BASDAI50=50% improvementfrom baseline in Bath Ankylosing Spondylitis Disease Activity Index.

FIGS. 13A and 13B depict the Week 14 results of the Phase 3non-radiographic axial spondyloarthritis (nr-axSpA) (SELECT AXIS-2)clinical trial for the primary endpoint ASAS40 response. FIG. 13Adepicts ASAS40 response for placebo vs. upadacitinib freebase 15 mg QDat Week 14; FIG. 13B depicts the ASAS40 response rate for placebo vs.upadacitinib freebase 15 mg QD over time (Baseline to Week 14). Theresults demonstrate the study met the primary endpoint. Upadacitinibshowed onset of effect in ASAS40 as early as Week 2. ASAS40=Assessmentof SpondyloArthritis International Society 40 Response; QD=once daily;PBO=placebo; UPA=upadacitinib freebase; *=significant after multiplicityadjustment.

FIGS. 14A-14F depict the Week 14 results of the Phase 3 non-radiographicaxial spondyloarthritis (nr-axSpA) (SELECT AXIS-2) clinical trial forkey clinical efficacy endpoints for placebo vs 15 mg upadacitinibfreebase once daily. FIG. 14A depicts the ASAS20, ASAS40, ASAS PartialRemission, and BASDAI50 responses at Week 14; FIG. 14B depicts the ASDASInactive Disease and ASDAS Low Disease Activity responses at Week 14;FIG. 14C depicts the ASDAS (CRP), Total Back Pain, Nocturnal Back Pain,and BASFI responses at Week 14; FIG. 14D depicts the MRI SPARCC Spinescore and the MRI SPARCC Sacroliac Joint Score at Week 14; FIG. 14Edepicts the ASQoL and ASAS Health Index scores at Week 14; and FIG. 14Fdepicts the BASMI and MASES scores at Week 14. PBO=placebo;UPA=upadacitinib freebase; ASDAS=Ankylosing Spondylitis Disease ActivityScore; BASDAI50=50% improvement from baseline in Bath AnkylosingSpondylitis Disease Activity Index; BASFI=Bath Ankylosing SpondylitisFunctional Index; MRI=magnetic resonance imaging;SPARCC=Spondyloarthritis Research Consortium of Canada; ASQoL=AnkylosingSpondylitis Quality of Life score; ASAS=Assessment of SpondyloArthritisInternational Society; BASMI=Bath Ankylosing Spondylitis MetrologyIndex; MASES=Maastricht Ankylosing Spondylitis Enthesitis Score;BL=Baseline; *=significant after multiplicity-adjustment.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention andalso to enable any person skilled in the art to practice the invention,including making and using any of the disclosed solid state forms orcompositions, and performing any of the disclosed methods or processes.The patentable scope of the invention is defined by the claims, and mayinclude other examples that occur to those skilled in the art. Suchother examples are intended to be within the scope of the claims if theyhave elements that do not differ from the literal language of theclaims, or if they include equivalent elements.

I. Definitions

Section headings as used in this section and the entirety of thedisclosure are not intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The term “subject” refers to a human subject.

The terms “treating” and “treatment” refer to ameliorating, suppressing,eradicating, reducing the severity of, decreasing the frequency ofincidence of, preventing, reducing the risk of, slowing the progressionof damage caused by or delaying the onset of the condition or improvingthe quality of life of a patient suffering from the condition.

The abbreviation “% CV” refers to the coefficient of variation,expressed as a percent. % CV is calculated according to the followingequation: % CV=(SD/x)*100, wherein x is the mean value and SD is thestandard deviation.

As used herein, the term “entry into a use environment” means contact ofa formulation of the disclosure with the gastric fluids of the subjectto whom it is administered, or with a fluid intended to simulate gastricfluid.

The abbreviation “MTX” refers to methotrexate.

Clinical Endpoint Definitions

Assessment of SpondyloArthritis International Society (ASAS), ASAS20,ASAS40, ASAS-PR, and ASAS 5/6 Responses.

Domains used for the ASAS responses are as follows:

-   -   a. Patient's Global Assessment—Represented by the PtGA-disease        activity (NRS score 0-10)    -   b. Pain—Represented by the Patient's Assessment of Total Back        Pain (Total Back Pain, NRS score 0-10)    -   c. Function—Represented by the BASFI (NRS score 0-10)    -   d. Inflammation—Represented by the mean of the 2 morning        stiffness-related BASDAI (mean of Questions 5 and 6 of the        BASDAI NRS score 0-10)

ASAS20 Response: Improvement of ≥20% and absolute improvement of ≥1 unit(on a scale of 0 to 10; 0=no pain and 10=worst possible pain) fromBaseline in ≥3 of the above 4 domains above, with no deterioration(defined as a worsening of ≥20% and a net worsening of ≥1 unit) in thepotential remaining domain.

ASAS40 Response: Improvement of ≥40% and absolute improvement of ≥2units (on a scale of 0 to 10; 0=no pain and 10=worst possible pain) fromBaseline in ≥3 of the above 4 domains above, with no deterioration(defined as a net worsening of >0 units) in the potential remainingdomain.

ASAS partial remission (PR): an absolute score of <2 units (on a scaleof 0 to 10; 0=no pain and 10=worst possible pain) from Baseline for eachof the 4 domains above.

ASAS 5/6 Response: Improvement of ≥20% from Baseline in 5 out of thefollowing 6 domains: BASFI, Patient's Assessment of Total Back Pain,PtGA-disease activity, inflammation (mean of Questions 5 and 6 of theBASDAI]), lateral lumbar flexion from BASMI, and hs-CRP.

ASAS Health Index (HI)

The ASAS HI is a linear composite measure with a dichotomous responseoption: “I agree” and “I do not agree” to a listing of 17 Questions.Each statement on the ASAS HI is given a score of “1”=“I agree” or“0”=“I do not agree.” The total sum of the ASAS HI ranges from 0-17,with a lower score indicating a better health status. Questions 7 and 8are not applicable to all patients. For those patients who ticked theresponse “not applicable,” the sum score is analyzed based on n=16 orn=15 respectively. A total score can be analyzed if no more than 20% ofthe data (i.e., 3 Questions) are missing. The total score is calculatedas follows for respondents with up to a maximum of three missingresponses: Sum.score=x/(17−m)*17, where x is the Question summationscore and m is the number of missing Questions and m≤3. Cases with morethan three missing responses (m>3) cannot be allocated a total score andthe total score will be set as missing. The 17 ASAS Health IndexQuestions are as follows:

1. Pain sometimes disrupts my normal activities.

2. I find it hard to stand for long.

3. I have problems running

4. I have problems using toilet facilities.

5. I am often exhausted.

6. I am less motivated to do anything that requires physical effort.

7. I have lost interest in sex.

8. I have difficulty operating the pedals in my car.

9. I am finding it hard to make contact with people.

10. I am not able to walk outdoors on flat ground.

11. I find it hard to concentrate.

12. I am restricted in traveling because of my mobility.

13. I often get frustrated.

14. I find it difficult to wash my hair.

15. I have experienced financial changes because of my rheumaticdisease.

16. I sleep badly at night.

17. I cannot overcome my difficulties.

Ankylosing Spondylitis Disease Activity Score (ASDAS)

Parameters used for the calculation of ASDAS:

-   -   1. Patient's Assessment of Total Back Pain (BASDAI Question 2        NRS score 0-10),    -   2. Duration of morning stiffness (BASDAI Question 6 NRS score        0-10),    -   3. Patient global assessment of disease activity (PtGA NRS score        0-10),    -   4. Peripheral pain/swelling (BASDAI Question 3 NRS score 0-10),        and    -   5. high-sensitivity C reactive protein (hsCRP) (in mg/mL) or        erythrocyte sedimentation rate (ESR).

Calculation of ASDAS:ASDAS_(hs-CRP)=0.121×total back pain+0.110×PtGA+0.073×peripheralpain/swelling+0.058×duration of morning stiffness+0.579×Ln(hs-CRP+1).ASDAS_(ESR)=0.113×patient global+0.293×√ESR+0.086×peripheralpain/swelling+0.069×duration of morning stiffness+0.079×total back pain.

To calculate observed ASDAS scores, the observed component value will becalculated first. Then the components will be included in thecalculation per the ASDAS formula. If any observed component is missingin a window, then the observed ASDAS score will be missing.

When the conventional CRP is below the limit of detection or when thehigh sensitivity CRP is <2 mg/L, the constant value of 2 mg/L should beused to calculate ASDAS-CRP.

ASDAS score is categorized by the following ASDAS Disease ActivityStates:

-   -   ASDAS Inactive Disease (ID): ASDAS<1.3    -   ASDAS Moderate Disease: 1.3≤ASDAS<2.1    -   ASDAS Low Disease Activity (LDA): ASDAS<2.1    -   ASDAS High Disease: 2.1≤ASDAS≤3.5    -   ASDAS Very High Disease: ASDAS>3.5

ASDAS Response categories are defined as follows:

-   -   ASDAS Major Improvement (MI) (a change from baseline ≤−2.0;        ≥2-point decrease from baseline)    -   ASDAS Clinically Important Improvement (CII) (a change from        baseline ≤−1.1; (≥1.1-point decrease from baseline)        Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL)

Each of the 18 statements on the ASQoL (provided below) is given a scoreof “1” (yes) or “0” (no). Concepts measured include activities of dailylife, emotional functioning, pain, fatigue, and sleep problems. A scoreof “1” is given where the Question is affirmed (with a “yes” answer),indicating adverse QoL. All Question scores are summed to give a totalscore or index. Scores can range from 0 (good QoL) to 18 (poor QoL),with higher scores equaling worsening functioning. Cases with more thanthree missing responses (i.e., more than 20%) cannot be allocated atotal score. For cases with between one and three missing responses, thetotal score is calculated as follows: T=18x/18−m where: T is the totalscore, x is the total score for the Questions affirmed and m is thenumber of missing Questions.

1. My condition limits the places I can go

2. I sometimes feel like crying

3. I have difficulty dressing

4. I struggle to do jobs around the house

5. It's impossible to sleep

6. I am unable to join in activities with my friends/family

7. I am tired all the time

8. I have to keep stopping what I am doing to rest

9. I have unbearable pain

10. It takes a long time to get going in the morning

11. I am unable to do jobs around the house

12. I get tired easily

13. I often get frustrated

14. The pain is always there

15. I feel I miss out on a lot

16. I find it difficult to wash my hair

17. My condition gets me down

18. I worry about letting people down

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI 50Response, and the Morning Stiffness Score

The BASDAI consists of a 1 through 10 scale (1 being no problem and 10being the worst problem) and is used to answer 6 questions pertaining tothe 5 symptoms: Fatigue, Spinal pain, Joint pain/swelling, Areas oflocalized tenderness (also called enthesitis, or inflammation of tendonsand ligaments), Morning stiffness duration, and Morning stiffnessseverity. A lower score indicates less disease activity.

The six BASDAI Questions (Components) are as follows:

-   -   Q1. How would you describe the overall level of        fatigue/tiredness you have experienced?    -   Q2. How would you describe the overall level of AS neck, back or        hip pain you have had?    -   Q3. How would you describe the overall level of pain/swelling in        joints, other than neck, back or hips you have had?    -   Q4. How would you describe the overall level of discomfort you        have had from any areas tender to touch or pressure?    -   Q5. How would you describe the overall level of morning        stiffness you have had from the time you wake up?    -   Q6. How long does your morning stiffness last from the time you        wake up?

Questions 1 through 5 have responses that can range from 0 (none) to 10(very severe); Question 6 have response range from 0 (0 hr) to 10 (2 ormore hrs), with 5 representing 1 hr.

Scoring of the BASDAI: BASDAI will be reported 0 to 10. The score has amaximum value of 10 and is calculated as follows:BASDAI Score=0.2(Q1+Q2+Q3+Q4+Q5/2+Q6/2)

If one of the 5 Questions (Questions 1-Question 4, inflammation) ismissing, then the score is the mean of the 4 non-missing Questions(total of 4 non-missing Questions divided by 4). If more than 1 of the 5Questions is missing, then the BASDAI score is missing. Question 5 andQuestion 6 jointly constitute Question 5 (inflammation). If bothQuestions 5 and 6 are missing, and questions 1 through 4 arenon-missing, then only one Question will be considered missing. TheBASDAI score can still be calculated as the mean of Questions 1-4.However, if, for example, both Question 6 and Question 1 are missing,then 2 Questions will be considered missing, as the inflammationcalculation would be incomplete. The BASDAI score would then beconsidered missing in this case.

A BASDAI 50 response is a categorical response based on BASDAI thatrepresents an at least 50% improvement from baseline in BASDAI.

The Morning Stiffness Score is the average of BASDAI Questions 5 and 6,and it ranges from 0-10.

A “change from baseline in BASDAI and BASDAI Questions (Components),including change from baseline in mean of Question 5 and 6 of theBASDAI” means (1) a change from baseline from the BASDAI Score, (2) achange from baseline in all of the BASDAI Questions, and (3) a changefrom baseline of the mean of Questions 5 and 6 (which representinflammation).

Bath Ankylosing Spondylitis Functional Index (BASFI)

The BASFI consists of the following 10 questions, assessing ability toperform activities such as dressing, bending, reaching, turning, andclimbing steps, each with a response ranging from 0 (easy) to 10(impossible):

1. Putting on your socks or tights without help or aids (e.g.,sock-aid).

2. Bending forward from the waist to pick up a pen from the floorwithout an aid.

3. Reaching up to a high shelf without help or aids (e.g., helpinghand).

4. Getting up out of an armless dining room chair without using yourhands or any other help.

5. Getting up off the floor without help from lying on your back.

6. Standing unsupported for 10 minutes without discomfort.

7. Climbing 12 to 15 steps without using a handrail or walking aid. Onefoot on each step.

8. Looking over your shoulder without turning your body.

9. Doing physically demanding activities (e.g., physiotherapy,exercises, gardening, or sports).

10. Doing a full day's activities whether at home or at work.

See, e.g., Sieper et al., Ann Rheum Dis (2009) 68 (Suppl II): ii1-ii44.doi:10.1136/ard.2008.104018.

Scoring of BASFI. The BASFI score will be derived based on the averageof Questions 1 through 10. If up to 2 Questions are missing,corresponding scores will be replaced with the mean of the remainingnon-missing Questions. If 3 or more Questions are missing, BASFI will beconsidered missing.

Bath Ankylosing Spondylitis Metrology Linear Index (BASMI_(lin))

The Linear BASMI (BASMI_(lin)) composite score will be calculated usingthe BASMI components. The table below presents the components ofBASMI_(lin) and assessment ranges for score.

TABLE 1 Components of BASMI_(lin) 0 Between 0 and 10 10 Lateral Lumbar A≥ 21.1 (21.1 − A)/2.1 A ≤ 0.1 flexion (cm) Tragus to wall A ≤ 8  (A −8)/3 A ≥ 38 distance (cm) Lumbar flexion A ≥ 7.4  (7.4 − A)/0.7 A ≤ 0.4(modified Schober) (cm) Intermalleolar A ≥ 124.5 (124.5 − A)/10  A ≤24.5 distance (cm) Cervical A ≥ 89.3 (89.3 − A)/8.5 A ≤ 4.3 rotation (°)BASMI_(lin) = Assessment measurements for tragus to wall, cervicalrotation and lateral lumbar flexion are the means of the left and rightmeasurement; A = assessment measurement

Scores for each assessment range from 0 to 10, and the BASMI_(lin) totalscore will be the average of the 5 assessment scores. If 1 Question ismissing, the BASMI_(lin) will be calculated as the mean of remaining 4Questions. Hence, the range of the BASMI_(lin) total score should bebetween 0 and 10. If 2 or more Questions are missing, then theBASMI_(lin) score will be considered missing. See e.g., van der Heijdeet al., Arth. Care & Res. (2012) 64:1919-1922 and van der Heijde et al.,Ann Rheum Dis (2008) 67:489-93.

Enthesitis Scoring: Spondyloarthritis Research Consortium of Canada(SPARCC) Enthesitis Index, Leeds Enthesitis Index (LEI), TotalEnthesitis Count, and Maastricht Ankylosing Spondylitis Enthesitis Score(MASES)

For the Spondyloarthritis Research Consortium of Canada (SPARCC)Enthesitis Index, 16 sites are evaluated as indicated in rows 1-8 in thetable below. Tenderness on examination is recorded as either present(coded as 1), absent (coded as 0), or not assessed (NA) for each site.The SPARCC enthesitis index is calculated by taking the sum of thescores from the 16 sites. The SPARCC score ranges from 0 to 16.

The Leeds Enthesitis Index evaluates enthesitis at the 6 entheseal sitesindicated in rows 2, 7 and 9 in the table below. Tenderness onexamination is recorded as either present (coded as 1), absent (coded as0), or not assessed (NA) for each of the 6 sites. The LEI is calculatedby taking the sum of the scores from the 6 sites. The LEI ranges from 0to 6.

The Total Enthesitis Count is calculated by taking the sum of thetenderness scores from all 18 sites in the table below.

The proportion of subjects with resolution of enthesitis sites includedin the LEI is defined as the proportion of subjects with LEI=0; theproportion with resolution of the SPARCC Enthesitis Index and of thetotal enthesitis count are similarly defined (score=0).

TABLE 2 Tenderness in Left Tenderness in Right Present Absent NA PresentAbsent NA 1 Medial epicondyle 2 Lateral epicondyle 3 Supraspinatusinsertion into the greater tuberosity of humerus 4 Greater trochanter 5Quadriceps insertion into superior border of patella 6 Patellar ligamentinsertion into inferior pole of patella or tibial tubercle 7 Achillestendon insertion into calcaneum 8 Plantar fascia insertion intocalcaneum 9 Medial femoral condyle Present = 1; Absent = 0; NA = Notassessed

The Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) will bemeasured to assess the presence (1) or absence (0) of enthesitis at 13different sites (first costochondral joint left/right, seventhcostochondral joint left/right, posterior superior iliac spineleft/right, anterior superior iliac spine left/right, iliac crestleft/right, fifth lumbar spinous process, and proximal insertion ofAchilles tendon left/right), noting the subjects' responses, yielding atotal score ranging 0-13. If one or more locations are missing, thescore will be calculated using available data. If all locations aremissing, then MASES is set to be missing.

EuroQoL-5D (EQ-5D-5L)

The EQ-5D-5L questionnaire is one of the most commonly usedquestionnaires to measure health-related quality of life. It consists ofa questionnaire and a visual analogue scale (VAS). The self-assessmentquestionnaire measures 5 dimensions of health status (mobility,self-care, usual activities, pain/discomfort, and anxiety/depression).The AS subject is asked to grade their own current level of function ineach dimension into 1 of 3 degrees of disability (severe, moderate, ornone). The PsA subject is asked to grade their own current level offunction in each dimension into 5 levels per dimension (no problems,slight problems, moderate problems, severe problems, and extremeproblems corresponding to Level 1 to Level 5 respectively) and includesthe EQ Visual Analogue Scale (EQ VAS). The 5 dimensions of health statusare converted into a single index value. Using the VAS, subjects recordperceptions of current perceived health status with a grade ranging from0 (the worst possible health status) to 100 (the best possible healthstatus).

High-Sensitivity C Reactive Protein (hs-CRP)

C-reactive protein (CRP), which is measured in blood plasma, is an acutephase protein that appears in blood circulation in response toinflammation, and serves as a biomarker for systemic inflammation.However, routine methods of CRP detection (turbidimetric, nephelometric)demonstrated poor sensitivity in detecting concentrations of CRP below6-10 mg/litre. See, e.g., Poddubnyy et al., Ann. Rheum. Dis. (2010)69:1338-1341.

The high-sensitivity C-reactive protein (hs-CRP) assay is a more precisemeasurement than routine CRP. Several different tests may be used tomeasure the hs-CRP normal range versus abnormal value for the subject tobe treated; thus the upper limit of normal (ULN) will be determined bythe laboratory for the hs-CRP test used and may differ from laboratoryto laboratory.

Joint Count Assessment: SJC and TJC

Swollen Joint Count Assessment (SJC or SJC66): An assessment of 66joints will be done by physical examination. The joints to be examinedfor swelling are the same as those examined for tenderness, except thehip joints are excluded. Joint swelling will be classified as present(“1”), absent (“0”), replaced (“9”), or no assessment (“NA”). Jointsinjected with corticosteroid will be considered non-evaluable for 90days from the time of the injection. The range for SJC66 will be 0 to66.

Tender Joint Count Assessment (TJC or TJC68): An assessment of 68 jointswill be done for tenderness by pressure manipulation on physicalexamination. Joint pain/tenderness will be classified as: present (“1”),absent (“0”), replaced (“9”), or no assessment (“NA”). Joints injectedwith corticosteroid will be considered non-evaluable for 90 days fromthe time of the injection. The range for TJC68 will be 0 to 68.

Anatomical joints are evaluated for swelling and tenderness at everystudy visit. The 34 anatomical joints in the below table are assessed inthis study for both the left and right side of the body.

TABLE 3 Anatomical Joints Assessed for Calculation of Tender and SwollenJoint Counts (TJC68 and SJC66) Temporomandibular SternoclavicularAcromio-clavicular Shoulder Elbow Wrist Metacarpophalangeal IMetacarpophalangeal II Metacarpophalangeal MetacarpophalangealMetacarpophalangeal Thumb III IV V Interphalangeal Proximal ProximalProximal Proximal Interphalangeal II Interphalangeal III InterphalangealIV Interphalangeal V Distal Distal Distal Distal Interphalangeal IIInterphalangeal III Interphalangeal IV Interphalangeal V Hip^(a) KneeAnkle Tarsus Metatarsophalangeal I Metatarsophalangeal IIMetatarsophalangeal Metatarsophalangeal III IV Metatarsophalangeal VGreat Toe/Hallux Interphalangeal II Interphalangeal III InterphalangealIV Interphalangeal V ^(a)Hip joints are not assessed for swelling.Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)

The mSASSS is a scoring method that measure radiographic progression inthe spine of patients with ankylosing spondylitis. The mSASSS has arange of 0 to 72, which is derived from scoring the anterior site of thelumbar spine from the lower border of T12 to the upper border of S1 andthe anterior site of the cervical spine from the lower border of C2 tothe upper border of T1 as either 0 (normal), 1 (erosion, sclerosis, orsquaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or NAvertebral body not evaluable. X-ray of spinal films will be analyzed forradiographic progression (from Baseline to the follow-up timepoint).

SpondyloArthritis Research Consortium of Canada (SPARCC) Assessment forSpine (MRI SPARCC—Spine or MRI-Spine SPARCC) and Sacroiliac (SI) Joints(MRI SPARCC—Joints or MRI-SI Joints SPARCC)

SPARCC scores for spine and sacroiliac (SI) joints are calculated byadding up the dichotomous outcomes from evaluations of the presence,depth and intensity of bone marrow edema lesions of the spine and SIjoints, respectively.

In the MRI SPARCC score of Spine, the entire spine is evaluated foractive inflammation (bone marrow edema) using the Short-TI InversionRecovery (STIR) image sequence. 23 discovertebral units (DVUs) areassessed, and the six most severely affected DVUs are selected and usedto calculate the MRI Spine SPARCC score. For each of the six DVUs, 3consecutive sagittal slices are assessed in four quadrants in order toevaluate the extent of inflammation in all three dimensions:

-   -   1. Each quadrant is scored for presence of increased signal on        STIR (1=increased signal; 0=normal signal)    -   2. Presence, on each of the sagittal slices, of a lesion        exhibiting high signal intensity (comparable to cerebrospinal        fluid) in any disco-vertebral unit is given an additional score        of 1.    -   3. Slices that included a lesion demonstrating continuous        increased signal of depth ≥1 cm extending from the endplate are        to be scored as +1 per slice.

The maximum possible score for any individual slice is 6, with a maximumscore for all 6 discovertebral units being 108.

The MRI SPARCC score of SI joints is conducted on 6 consecutive slicesof the STIR image sequence. All lesions within the iliac bone and withinthe sacrum up to the sacral foramina are to be scored. The SI joint isdivided into 4 quadrants: upper iliac, lower iliac, upper sacral andlower sacral. Each consecutive slice is scored separately for the rightand left joint in all four quadrants as follows:

-   -   1. Each quadrant is scored for presence of increased signal on        STIR (1=increased signal; 0=normal signal)    -   2. Joints that include a lesion exhibiting intense signal on the        STIR sequence are scored as +1 per slice.    -   3. Joints that included a lesion demonstrating continuous        increased signal of depth ≥1 cm from the articular surface are        be scored as +1 per slice.

The maximum possible score for any individual slice is 12, with amaximum score for all 6 slices being 72.

36-Item Short Form Health Survey (Form SF-36)

The 36-Item Short Form, Version 2 (SF-36v2) (Quality Metric) healthsurvey consists of 36 general health questions. It has 2 components:physical and mental. For each component, a transformed summary score iscalculated using 8 sub domains: physical functioning, role-physical,bodily pain, general health, vitality, social functioning,role-emotional, and mental health. The range is from 0 to 100, withhigher scores indicating better outcomes. The coding and scoring for theSF-36 will use the software provided by the vendor.

Additional Definitions

A “subject” means a human. The terms “patient” and “subject” are usedinterchangeably herein.

An “adult subject” means a subject 18 years or older.

A “juvenile” or “pediatric” subject means a subject 1 to <18 years old.Juvenile subjects to be treated are subjects diagnosed with juvenile AS(JAS), juvenile PsA (JPsA), and/or juvenile PsO (JPsO) and in need oftreatment as determined by a physician (“active juvenile AS” and “activejuvenile PsA”, “active juvenile PsO”, respectively). Juvenile AS may beclassified per International League of Associations for Rheumatology(ILAR) (defining 7 discrete categories of arthritis starting before theage of 18 years: systemic arthritis, oligoarthritis, polyarthritis(rheumatoid factor [RF]-negative), polyarthritis (RF-positive), PsA,enthesitis-related JIA (or juvenile enthesitis-related arthritis [ERA]),and undifferentiated arthritis). See, e.g., Petty et al., J Rheumatol.(2004) 31:390-2. Juvenile PsA may be classified per pediatricInternational League of Associations for Rheumatology (ILAR) and/oradult criteria [Classification criteria for Psoriatic Arthritis(CASPAR)]. See e.g., Aviel et al., Pediatric Rheumatology (2013) 11:11;Zisman et al., J. Rheum. (2017) 44:342-351.

The “2009 ASAS classification criteria” for the classification of asubject with axial spondyloarthritis (axial SpA, or axSpA) is describedin Rudwaleit et al., Ann. Rheum. Dis. (2009) 68:777-783. The criteriarequire chronic back pain (≥3 months) in the subject and age at onset<45 years, with the subject also having the following conditions (1) thepresence of sacroiliitis by radiography or by magnetic resonance imaging(MRI) plus at least one SpA feature (“imaging arm”) or (2) the presenceof human leukocyte antigen (HLA) B27 plus at least two SpA features(“clinical arm”). Sacroiliitis on imaging refers to active (acute)inflammation on MRI highly suggestive of sacroiliitis associated withSpA, or definite radiographic sacroiliitis. SpA features are selectedfrom the group consisting of inflammatory back pain, arthritis,enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn's disease orulcerative colitis, good response to NSAISs (24-48 hours after a fulldose of an NSAID the back pain is not present any more or is muchbetter), family history for SpA, positive HLA-B27, and elevatedC-reactive protein (above the upper normal limit in the presence of backpain, and after exclusion of other reasons for elevation). See alsoDeodhar et al., Arth. & Rheum. (2014) 66:2649-2656.

The “1984 modified New York criteria” for the classification of asubject with ankylosing spondylitis (AS), is described in van der Lindenet al., Arthritis and Rheumatism (1984) 27:361-368, and has twocomponents: diagnosis and grading; the diagnosis component further hastwo criteria: clinical and radiologic. The clinical criteria require:(i) low back pain and stiffness for more than 3 months which improveswith exercise, but is not relieved by rest; (ii) limitation of motion ofthe lumbar spine in both the sagittal and frontal planes, and (iii)limitation of chest expansion relative to normal values corrected forage and sex. The radiologic criterion requires sacroiliitis grade ≥2bilaterally or sacroiliitis grade 3-4 unilaterally. The gradingcomponent requires: (i) definite ankylosing spondylitis if theradiologic criterion is associated with at least 1 clinical criterion;and (ii) probable ankylosing spondylitis if 3 clinical criteria arepresent, and the radiologic criterion is present without any signs orsymptoms satisfying the clinical criteria. See also Deodhar et al.,Arth. & Rheum. (2014) 66:2649-2656.

The term “axial Spondyloarthritis” (axial SpA or axSpA) encompasses both“ankylosing spondylitis” (AS) and “non-radiographic axialspondyloarthritis” (nr-axial SpA, or nr-axSpA). A subject with “activeaxial Spondyloarthritis” (active axSpA) means a subject with a clinicaldiagnosis of active AS or active nr-axial SpA, and in need of treatmentas determined by a physician.

A subject with “active ankylosing spondylitis” (active AS) means asubject with a clinical diagnosis of AS and in need of treatment asdetermined by a physician. In certain embodiments, the subject diagnosedas suffering from AS is further classified (e.g., in the United States)as fulfilling the 1984 modified New York Criteria for AS and/or asfulfilling the 2009 ASAS classification criteria. In certainembodiments, the subject with a high disease activity of AS has a BathAnkylosing Spondylitis Disease Activity Index score ≥4 and/or ASDAS ≥2.1and/or a Patient's Assessment of Total Back Pain (Total Back Pain score)≥4 based on a 0-10 numerical rating scale at baseline. See, e.g., vander Heijde et al., Ann Rheum Dis. (2017)76:978-991; Sieper andPoddubnyy, Lancet (2017) 73-84.

A subject with “active non-radiographic axial spondyloarthritis” (activenr-axial SpA or active nr-axSpA) means a subject with a clinicaldiagnosis of nr-axial SpA and in need of treatment as determined by aphysician. In certain embodiments, the subject diagnosed as sufferingfrom nr-axial SpA is further classified (e.g., in the United States) asfulfilling the 2009 ASAS classification criteria for axSpA but notmeeting the radiologic criterion of the 1984 modified New York criteriafor AS. In certain embodiments, the subject with high disease activityof nr-axial SpA has a Bath Ankylosing Spondylitis Disease Activity Indexscore ≥4 and/or an ASDAS ≥2.1 and/or a Patient's Assessment of TotalBack Pain Score (Total Back Pain score) ≥4 based on a 0-10 numericalrating scale at baseline; and an objective sign of inflammatory activityselected from the group consisting of (i) an objective sign of activeinflammation on MRI of SI joints or (ii) hsCRP>upper limit of normal(ULN) at baseline. See, e.g., van der Heijde et al., Ann Rheum Dis.(2017) 76:978-991Sieper et al. Ann. Rheum. Dis. (2009) 68 Suppl2:ii1-44. doi: 10.1136/ard.2008.104018; Van der Heijde et al. Ann RheumDis. (2017) 76:978-991; Sieper and Poddubnyy, Lancet (2017) 73-84.

The abbreviation “AS” refers to ankylosing spondylitis.

A result being achieved “within X weeks” of administration of the firstdose of the JAK1 inhibitor wherein X is a integer greater than 0 (e.g.,1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 52, 64 weeks, etc.) meansthe result occurs within the time frame beginning at the time of theadministration of the first dose (Week 0) of the JAK1 inhibitor, andending on and including the last day of the given specified week. Ameasurement or score used to determine if a result is achieved “at weekX” (e.g., at week 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 52, 64weeks, etc.) may be taken at any point during, as well as on andincluding the first and last day, of given week X for the subject.

The abbreviation “axSpA” refers to axial spondyloarthritis.

The abbreviations “bDMARDs” and “biologic DMARDs” refer to biologicDisease Modifying Anti-Rheumatic Drugs. Examples of bDMARDs include, butare not limited to, biologic tumor necrosis factor inhibitors (e.g.,adalimumab, etanercept) and interleukin (IL)-17 inhibitors (e.g.,secukinumab, ixekizumab).

The term “bDMARD-IR” refers to a subject who is a bDMARD inadequateresponder. bDMARD-IR subjects include those who have had an inadequateresponse to treatment with at least one bDMARD, or who have anintolerance to or contraindication for bDMARDs. Subjects who arebDMARD-IR include subjects who have discontinued treatment with at leastone bDMARD due to intolerance or lack of efficacy.

The term “bDMARD naïve” refers to a subject who has not had priorexposure to any biologic therapy, including any bDMARD, that maypotentially have a therapeutic impact on the disorder or condition thatis being treated.

The term “baseline” or “BL” refers to the time immediately before firstdosing with the JAK1 inhibitor. Baseline measurements (i.e., on the“Baseline Visit” or on the “Screening Visit”) are collected prior toadministration of the first dose of the JAK1 inhibitor (i.e.,upadacitinib freebase or a pharmaceutically acceptable salt thereof),and may include a measurement taken the day of but prior to first dosingwith the JAK1 inhibitor.

The term “change from baseline” for a particular score or measurementmeans the score or measurement has improved (e.g., demonstrating apositive clinical effect in the subject or population of subjects) ascompared to the score or measurement taken at baseline.

The abbreviation “CII” means Clinically Important Improvement.

The phrase “concomitant administration” or “concomitant treatment” whenreferencing a therapy in addition to administration of the JAK1inhibitor means the additional therapy is occurring at baseline and/orduring treatment with the JAK1 inhibitor.

The abbreviations “DMARDs” and “non-biologic DMARDs” refer tonon-biologic Disease Modifying Anti-Rheumatic Drugs. Non-biologic DMARDsinclude, but are not limited to, methotrexate (MTX), sulfasalazine(SSZ), leflunomide (LEF), apremilast, hydroxychloroquine (HCQ),bucillamine, and iguratimod. “Non-biologic DMARDs” and“conventional-synthetic disease modifying anti-rheumatic drugs”(csDMARDs) are used interchangeably herein.

The term “DMARD-IR” or “non-biologic DMARD-IR” refers a subject who is anon-biologic DMARD inadequate responder. DMARD-IR subjects include thosewho have had an inadequate response to treatment with at least onenon-biologic DMARD, or who have an intolerance to or contraindicationfor non-biologic DMARDs.

The abbreviation “EMA” means European Medicines Agency.

The abbreviation “FDA” means Food and Drug Administration.

The abbreviation “hsCRP” means high-sensitivity C-reactive protein.

The abbreviation “ID” means Inactive Disease.

The phrase “improving physical function” in a subject with active PsAmeans an improvement in activities or tasks compared to baseline.

“In need of treatment” or “in need of treatment . . . as determined by aphysician” refers to the physician's opinion that, at baseline, thecondition is not sufficiently well-controlled, such as by other medicalmanagement (e.g., by other therapy or therapies previously administeredto treat the condition).

The phrase “inhibiting the progression of structural damage” or“preventing structural progression” in a subject with active PsA meansdemonstrating prevention of bony changes on x-ray compared to baseline.

“JAK1 inhibitor” refers to the compound upadacitinib((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide)freebase or a pharmaceutically acceptable salt thereof. Solid stateforms of the JAK1 inhibitor are further described herein.

The abbreviation “LDA” means low disease activity.

The abbreviation “MI” means major improvement.

The abbreviation “MRI” means magnetic resonance imaging.

A result is considered “non-inferior” (NI) as compared to adalimumab ifadministration of the JAK1 inhibitor preserves at least 50% of theplacebo-subtracted adalimumab effect.

The abbreviation “nr-axSpA” refers to non-radiographic axialspondyloarthritis.

The abbreviation “NRI” means non-responder imputation.

The abbreviation “NSAIDs” refers to non-steroidal anti-inflammatorydrugs. Examples NSAIDs include, but are not limited to, traditionalNSAIDs (e.g., ibuprofen) and salicylates (e.g., aspirin).

The term “pharmaceutically acceptable” (such as in the recitation of a“pharmaceutically acceptable salt” or a “pharmaceutically acceptablediluent”) refers to a material that is compatible with administration toa human subject, e.g., the material does not cause an undesirablebiological effect. Examples of pharmaceutically acceptable salts aredescribed in “Handbook of Pharmaceutical Salts: Properties, Selection,and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).Examples of pharmaceutically acceptable excipients are described in the“Handbook of Pharmaceutical Excipients,” Rowe et al., Ed.(Pharmaceutical Press, 7th Ed., 2012).

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid,benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalicacid, tartaric acid such as mono tartaric acid (e.g., (+) or(−)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

A “population of subjects” refers to the group of subjects participatingin a clinical trial, with all subjects suffering from the same diseaseor symptom to be treated, wherein the clinical trial comprises atreatment arm (a subgroup of the subjects treated with the JAK1inhibitor), and a placebo arm (a subgroup of the subjects not treatedwith the JAK1 inhibitor). When used in connection with the treatment ofa population of subjects, the phrase “at least X % of the subjects inthe treated population achieve” a particular response refers to theplacebo corrected X % response (subjects treated—subjects not treated).

The abbreviation “PR” means partial remission.

The abbreviation “PsA” refers to psoriatic arthritis.

The abbreviation “PsO” refers to psoriasis. Psoriasis includes psoriasisas a skin manifestation of PsA.

The abbreviation “QD” means once daily.

The phrase “reducing signs and symptoms” means an improvement in diseaseactivity, function, and/or quality of life compared to baseline.

The abbreviation “SI” means sacroiliac.

“Statistically significant” means when observed p value<alpha for agiven hypothesis testing. The pre-specified significance level, alpha,is the probability of rejecting the null hypothesis given that it istrue. Alpha is also called type I error or false positive rate. It isusually set at or below 0.05. The observed p value is the probability,under the null hypothesis, of observing an effect of the same magnitudeor more extreme. When observed p value<alpha, the null hypothesis isrejected, and statistical significance is claimed. In amultiplicity-controlled analysis, when the adjusted p value<alpha, theresult is statistically significant. In the fixed sequence of amultiplicity-controlled analysis, statistical significance can beclaimed for a lower ranked endpoint only if the previous endpoint in thesequence meets the requirements of statistical significance.

A result is considered “superior” as compared to adalimumab if themultiplicity adjusted p value for the null hypothesis testing of thetreatment difference between the JAK1 inhibitor and adalimumab is lessthan pre-specified significance level.

“Total spinal ankylosis” refers to bridging syndesmophytes (fusion) in atotal sum of ≥5 segments of the C2-T1 or T12-S1 spine (e.g., 2 segmentsfused in the cervical and 3 segments fused in the lumbar spine would beconsidered positive for total spinal ankylosis).

The terms “treating”, “treatment”, and “therapy” and the like, as usedherein, are meant to include but not limited to alleviation or relief ofone or more symptoms of the condition from which the subject issuffering (i.e., axial spondyloarthritis (axSpA) (e.g., non-radiographicaxSpA (nr-axSpA), ankylosing spondylitis (AS)), psoriatic arthritis(PsA), psoriasis (PsO)), including the slowing or cessation of theprogression of the condition, such as slowing or cessation of theprogression of structural damage associated with the condition, thestructural progression of the condition, and/or improving the physicalfunction of a subject suffering from the condition.

The term “upadacitinib freebase” refers to freebase (non-salt, neutral)forms of upadacitinib. Examples of upadacitinib freebase solid stateforms include amorphous upadacitinib freebase and crystalline freebasesof upadacitinib, such as crystalline freebase solvates, crystallinefreebase hydrates, crystalline freebase hemihydrates, and crystallinefreebase anhydrates of upadacitinib. Specific examples of upadacitinibfreebase solid state forms include but are not limited to AmorphousUpadacitinib Freebase, Upadacitinib Freebase Solvate Form A,Upadacitinib Freebase Hydrate Form B, Upadacitinib Freebase Hydrate FormC (which is a hemihydrate), and Upadacitinib Freebase Anhydrate Form D,each as described in WO 2017/066775 and WO 2018/165581.

The term “upadacitinib freebase equivalent” refers to the amount of theneutral upadacitinib freebase (active ingredient) administered, and notincluding any coformer (e.g., solvent or water molecule(s)) of a solvateor hydrate (including hemihydrate), and not including anypharmaceutically acceptable salt counter anions of a pharmaceuticallyacceptable salt. For example, 15.4 mg of crystalline upadacitinibfreebase hemihydrate (which includes 1/2 of a water conformer moleculeper upadacitinib freebase molecule) delivers 15 mg of upadacitinibfreebase equivalent, while 30.7 mg of crystalline upadacitinib freebasehemihydrate (which includes 1/2 of a water conformer molecule perupadacitinib freebase molecule) delivers 30 mg of upadacitinib freebaseequivalent.

II. Methods of Treatment

The present disclosure also relates to methods of treating aJAK-associated condition in a subject, particularly a human subjectsuffering from or susceptible to the condition, comprising administeringto the subject a therapeutically effective amount of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure. Anotheraspect of the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure for use intreatment of a JAK-associated condition in a subject, particularly in ahuman subject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or one or more solid state forms of Compound 1. In one aspect,the condition is a JAK-1-associated condition. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of immunomodulation,inflammation, and proliferative disorders (such as cancer) in a subject,wherein the method comprises administering to the subject, particularlya human subject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of immunomodulation, inflammation,and proliferative disorders (such as cancer) in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,multiple sclerosis, experimental allergic encephalomyelitis, systemiclupus erythematosus, Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis,POEMS syndrome, and chronic fatigue syndrome in a subject, wherein themethod comprises administering to the subject, particularly a humansubject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, multiplesclerosis, experimental allergic encephalomyelitis, systemic lupuserythematosus, Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis,POEMS syndrome, and chronic fatigue syndrome in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis(including moderate to severe rheumatoid arthritis), systemic lupuserythematosus, multiple sclerosis, Crohn's disease (including moderateto severe Crohn's disease), psoriasis (including moderate to severechronic plaque psoriasis), ulcerative colitis (including moderate tosevere ulcerative colitis), ankylosing spondylitis, psoriatic arthritis,juvenile idiopathic arthritis (including moderate to severepolyarticular juvenile idiopathic arthritis), diabetic nephropathy, dryeye syndrome, Sjogren's syndrome, alopecia areata, vitiligo, and atopicdermatitis in a subject, wherein the method comprises administering tothe subject, particularly a human subject suffering from or susceptibleto the condition, a therapeutically effective amount of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis (includingmoderate to severe rheumatoid arthritis), systemic lupus erythematosus,multiple sclerosis, Crohn's disease (including moderate to severeCrohn's disease), psoriasis (including moderate to severe chronic plaquepsoriasis), ulcerative colitis (including moderate to severe ulcerativecolitis), ankylosing spondylitis, psoriatic arthritis, juvenileidiopathic arthritis (including moderate to severe polyarticularjuvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome,Sjogren's syndrome, alopecia areata, vitiligo, and atopic dermatitis ina subject, particularly in a human subject suffering from or susceptibleto the condition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of an ocular condition,systemic inflammatory response syndrome, juvenile rheumatoid arthritis,systemic onset juvenile rheumatoid arthritis, type III hypersensitivityreactions, type W hypersensitivity, inflammation of the aorta,iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy,diabetic retinopathy or microangiopathy, chronic inflammation,ulcerative colitis, inflammatory bowel disease, allergic diseases,dermatitis scleroderma, acute or chronic immune disease associated withorgan transplantation, psoriatic arthropathy, ulcerative coliticarthropathy, autoimmune bullous disease, autoimmune hemolytic anemia,rheumatoid arthritis associated interstitial lung disease, systemiclupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjogren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, andautoimmune thrombocytopenia in a subject, wherein the method comprisesadministering to the subject, particularly a human subject sufferingfrom or susceptible to the condition, a therapeutically effective amountof Compound 1 freebase or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting of an ocularcondition, systemic inflammatory response syndrome, juvenile rheumatoidarthritis, systemic onset juvenile rheumatoid arthritis, type IIIhypersensitivity reactions, type W hypersensitivity, inflammation of theaorta, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscularatrophy, diabetic retinopathy or microangiopathy, chronic inflammation,ulcerative colitis, inflammatory bowel disease, allergic diseases,dermatitis scleroderma, acute or chronic immune disease associated withorgan transplantation, psoriatic arthropathy, ulcerative coliticarthropathy, autoimmune bullous disease, autoimmune hemolytic anemia,rheumatoid arthritis associated interstitial lung disease, systemiclupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjogren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, andautoimmune thrombocytopenia in a subject, particularly in a humansubject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis,psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis,ankylosing spondylitis, alopecia areata, hidradenitis suppurativa,atopic dermatitis, and systemic lupus erythematosus in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a solid state form of Compound 1. Inone aspect, the solid state form is the Amorphous Freebase. In anotheraspect, the solid state form is the Freebase Hydrate Form B. In anotheraspect, the solid state form is the Freebase Hydrate Form C. In anotheraspect, the solid state form is the Tartrate Hydrate. In another aspect,the solid state form is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis,ulcerative colitis, systemic lupus erythematosus, lupus nephritis,diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopeciaareata, vitiligo, and atopic dermatitis in a subject, wherein the methodcomprises administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In another aspect, thepresent disclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting ofrheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriaticarthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus,lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren'ssyndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject,particularly in a human subject suffering from or susceptible to thecondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatingarthritis in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of Compound 1 freebase ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of arthritis in asubject, particularly in a human subject suffering from or susceptibleto arthritis, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the arthritis is selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis, andpsoriatic arthritis. In another aspect, the arthritis is rheumatoidarthritis. In another aspect, the arthritis is juvenile idiopathicarthritis. In another aspect, the arthritis is psoriatic arthritis. Inanother aspect, the solid state form is the Amorphous Freebase. Inanother aspect, the solid state form is the Freebase Hydrate Form B. Inanother aspect, the solid state form is the Freebase Hydrate Form C. Inanother aspect, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D. Inanother aspect, the solid state form is the Freebase Solvate Form A. Inanother aspect, the solid state form is the Hydrochloride Solvate formAA. In another aspect, the solid state form is the Hydrochloride SolvateForm BB. In another aspect, the solid state form is the HydrochlorideSolvate Form CC. In another aspect, the solid state form is theL-Maleate Form AAA. In another aspect, the solid state form is theL-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga spondyloarthropathy in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of spondyloarthropathy, particularly in a human subjectsuffering from or susceptible to spondyloarthropathy, the use comprisingadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In one aspect, the spondyloarthropathyis ankylosing spondylitis. In another aspect, the solid state form isthe Amorphous Freebase. In another aspect, the solid state form is theFreebase Hydrate Form B. In another aspect, the solid state form is theFreebase Hydrate Form C. In another aspect, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga gastrointestinal condition in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a gastrointestinal condition, particularly in a humansubject suffering from or susceptible to a gastrointestinal condition,the use comprising administering to the subject a therapeuticallyeffective amount of Compound 1 freebase or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1. In one aspect, thegastrointestinal condition is selected from the group consisting ofCrohn's disease and ulcerative colitis. In another aspect, thegastrointestinal condition is Crohn's disease. In another aspect, thegastrointestinal condition is ulcerative colitis. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Solvate Form A. In another aspect, the solidstate form is the Hydrochloride Solvate form AA. In another aspect, thesolid state form is the Hydrochloride Solvate Form BB. In anotheraspect, the solid state form is the Hydrochloride Solvate Form CC. Inanother aspect, the solid state form is the L-Maleate Form AAA. Inanother aspect, the solid state form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga skin condition, wherein the method comprises administering to thesubject a therapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a skin condition,particularly in a human subject suffering from or susceptible to a skincondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the skin condition is selected from the groupconsisting of psoriasis, plaque psoriasis, nail psoriasis, andhidradenitis suppurativa. In another aspect, the skin condition ispsoriasis. In another aspect, the skin condition is plaque psoriasis. Inanother aspect, the skin condition is nail psoriasis. In another aspect,the skin condition is hidradenitis suppurativa. In another aspect, theskin condition is atopic dermatitis. In another aspect, the solid stateform is the Amorphous Freebase. In another aspect, the solid state formis the Freebase Hydrate Form B. In another aspect, the solid state formis the Freebase Hydrate Form C. In another aspect, the solid state formis the Tartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

The therapeutically effective dose level for any particular subject willdepend upon the specific situation and can depend upon a variety offactors including the type, age, weight, sex, diet, and condition of thesubject being treated; the severity of the pathological condition;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the route of administration; the duration of the treatment;pharmacological considerations, such as the activity, efficacy,pharmacokinetic, and toxicology profiles of the particular compound orsalt used; whether a drug delivery system is utilized; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. An ordinarily skilledphysician provided with the disclosure of the present application willbe able to determine appropriate dosages and regimens for administrationof the therapeutic agent to the subject, and to adjust such dosages andregimens as necessary during the course of treatment, in accordance withmethods well-known in the therapeutic arts. It is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. Thus, the dosage regimenactually employed can vary widely, and therefore, can derive from thepreferred dosage regimen set forth below.

The total daily dose of the solid state form (administered in single ordivided doses) typically is from about 0.001 to about 100 mg/kg, or fromabout 0.001 to about 30 mg/kg, or from about 0.001 to about 15 mg/kg. Inanother embodiment, the total daily dose is from about 0.01 to about 10mg/kg (i.e., mg of the compound or salt per kg body weight). Dosage unitcompositions can contain such amounts or submultiples thereof to make upthe daily dose. In many instances, the administration of the compound orsalt will be repeated a plurality of times. Multiple doses per daytypically may be used to increase the total daily dose, if desired.

In one embodiment, the daily dose of the solid state form administeredto the subject is from about 0.01 mg to about 3000 mg. In one aspect,the daily dose is from about 0.1 mg to about 1000 mg. In another aspect,the daily dose is from is from about 1 mg to about 500 mg. In anotheraspect, the daily dose is from about 1 mg to about 250 mg. In anotheraspect, the daily dose is from about 1 mg to about 100 mg. In anotheraspect, the daily dose is from about 1 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 45 mg. In anotheraspect, the daily dose is from about 1 mg to about 30 mg. In anotheraspect, the daily dose is from about 1 mg to about 25 mg. In anotheraspect, the daily dose is from about 1 mg to about 24 mg. In anotheraspect, the daily dose is from about 1 mg to about 15 mg. In anotheraspect, the daily dose is from about 1 mg to about 7.5 mg. In anotheraspect, the daily dose is from about 25 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 10 mg. In anotheraspect, the daily dose is from about 10 mg to about 20 mg. In anotheraspect, the daily dose is from about 20 mg to about 30 mg. In anotheraspect, the daily dose is from about 30 mg to about 40 mg. In anotheraspect, the daily dose is from about 7.5 mg to about 45 mg. In anotheraspect, the daily dose is from about 15 mg to about 30 mg. In anotheraspect, the daily dose is about 3 mg. In another aspect, the daily doseis about 6 mg. In another aspect, the daily dose is about 7.5 mg. Inanother aspect, the daily dose is about 12 mg. In another aspect, thedaily dose is about 15 mg. In another aspect, the daily dose is about 18mg. In another aspect, the daily dose is about 24 mg. In another aspect,the daily dose is about 30 mg. In another aspect, the daily dose isabout 36 mg. In another aspect, the daily dose is about 45 mg.

In one embodiment, a dose of about 3 mg, about 6 mg, about 12 mg, orabout 24 mg per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 is administered orally BID (twice daily)in equal amounts (e.g., twice a day, about 3 mg each time) to a humansubject.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of a solid state form ofCompound 1. In one embodiment, the methods or uses compriseadministering orally QD (once daily) to a human subject a solid stateform of Compound 1 in an amount sufficient to deliver 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebaseequivalent to the subject. In one embodiment, the solid state form isthe Amorphous Freebase. In one embodiment, the solid state form is theFreebase Hydrate Form B. In one embodiment, the solid state form is theFreebase Hydrate Form C. In one embodiment, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 15 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of Compound 1freebase or a pharmaceutically acceptable salt thereof. The 24 mg QDdose of Compound 1 freebase or a pharmaceutically acceptable saltthereof may be administered as either a single dosage form comprisingabout 24 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, ortwo dosage forms comprising about 12 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof administered simultaneously.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of a solidstate form of Compound 1. In one embodiment, the methods or usescomprise administering orally QD (once daily) to a human subject a solidstate form of Compound 1 in an amount sufficient to deliver 24 mg ofCompound 1 freebase equivalent to the subject. The 24 mg QD dose of thesolid state form of Compound 1 may be administered as either a singledosage form comprising about 24 mg per unit dosage form (e.g., pertablet or capsule) of the solid state form of Compound 1, or two dosageforms comprising about 12 mg per unit dosage form (e.g., per tablet orcapsule) of the solid state form of Compound 1 administeredsimultaneously. In one embodiment, the solid state form is the AmorphousFreebase. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 30 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 36 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 45 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

Compound 1 freebase or a pharmaceutically acceptable salt thereof orsolid state forms thereof may be used alone, or in combination withmethotrexate or other non-biologic disease-modifying anti-rheumaticdrugs (DMARDs), and/or in combination with anti-TNFα biological agents,such as TNF antagonists like chimeric, humanized or human TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), golimumab such as SIMPONI™(golimumab), certolizumab pegol such as CIMZIA™, tocilizumab such asACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives,thereof, etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) orp55TNFR1gG (lenercept).

In certain embodiments, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or solid state forms thereof halt diseaseprogression, and/or relieves at least a symptom of the disease, whichmay be detected or monitored by X-ray results, including radiographicprogression of joint damage.

In certain embodiments, structural joint damage can be assessedradiographically and expressed as change in Total Sharp Score (TSS) andits components, the erosion score and Joint Space Narrowing (JSN) score,for example, at week 12 compared to baseline, or at week 24 as comparedto baseline.

In another embodiment, the adult subject is a subject who has had aninadequate response or intolerance to one or more disease-modifyingantirheumatic drugs (DMARDs). In one embodiment, the DMARD is aconventional synthetic DMARD (csDMARD). In another embodiment, the DMARDis a biologic DMARD (bDMARD). Examples of csDMARDs include, but are notlimited to, methotrexate (MTX), sulfasalazine, hydroxychloroquine,chloroquine, leflunomide, and azathioprine. Examples of bDMARDs include,but are not limited to, tocilizumab such as ACTEMRA™, etanercept such asp75TNFR1gG (ENBREL™ brand etanercept), adalimumab (such as HUMIRA™ brandadalimumab), and golimumab such as SIMPONI™ (golimumab). In oneembodiment, the csDMARD is MTX. In one embodiment, the bDMARD is ananti-TNF biologic. An inadequate response or intolerance to one or moreDMARDs can be measured using any of the indices described herein (e.g.,failure to achieve an ACR20 response). In one embodiment, a subjecthaving an inadequate response to a DMARD is a subject who does notachieve reduced disease activity, does not achieve an improvement inphysical function, exhibits no evidence of stopping disease progression,or who experiences disease relapse after treatment with the DMARD. Inone embodiment, a subject having an inadequate response to a DMARD is asubject who does not achieve an ACR20 response after treatment with theDMARD. In one embodiment, a subject having an inadequate tolerance(intolerance) to a DMARD is a subject who experiences toxicity orcomplicating co-morbidities after treatment with the DMARD.

In one embodiment, the adult subject is a subject who has had aninadequate response to stable methotrexate therapy. In one embodiment,the adult subject received methotrexate therapy for at least threemonths prior to treatment. In another embodiment, the adult subjectreceived a stable dose of methotrexate of about 7.5 to about 25 mg perweek for at least four weeks prior to treatment. In another embodiment,the adult subject is administered a stable dose of methotrexate (e.g.,from about 7.5 to about 25 mg per week) during treatment withCompound 1. In another embodiment, the adult subject received asupplement of folic acid for at least four weeks prior to treatment. Inanother embodiment, the adult subject is administered a supplement offolic acid during treatment.

In one embodiment, the adult subject is a subject who has had aninadequate response or intolerance to at least one anti-TNF therapy.Anti-TNF biologic agents are described elsewhere herein, and include TNFantagonists such as chimeric, humanized or human TNF antibodies,adalimumab (such as HUMIRA™ brand adalimumab), infliximab such as CA2(REMICADE™ brand infliximab), golimumab such as SIMPONI™ (golimumab),certolizumab pegol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP571, and soluble p55 or p75 TNF receptors, derivatives, thereof,etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) or p55TNFR1gG(lenercept). In one embodiment, the adult subject received methotrexatetherapy for at least three months prior to treatment. In anotherembodiment, the adult subject received a stable dose of methotrexate ofabout 7.5 to about 25 mg per week for at least four weeks prior totreatment. In another embodiment, the adult subject is administered astable dose of methotrexate (e.g., from about 7.5 to about 25 mg perweek) during treatment with Compound 1. In another embodiment, the adultsubject has been treated with at least one anti-TNF biologic agent forat least three months prior to treatment with Compound 1. In anotherembodiment, the adult subject received a supplement of folic acid for atleast four weeks prior to treatment. In another embodiment, the adultsubject is administered a supplement of folic acid during treatment

In certain embodiments, the adult subject, who has had an inadequateresponse or tolerance to one or more DMARDS (including methotrexateand/or an anti-TNF biologic agent), achieves an ACR20 response, an ACR50response, an ACR70 response, and/or a decrease in DAS28(CRP) as comparedto baseline following treatment for at least twelve weeks (e.g., at week12 of treating), and/or following treatment for at least 8 weeks (e.g.,at week 8 of treating), and/or following treatment for at least 6 weeks(e.g., at week 6 of treating), and/or following treatment for at least 4weeks (e.g., at week 4 of treating), and/or following treatment for atleast 2 weeks (e.g., at week 2 of treating).

In another embodiment, the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms of Compound 1 used inany of the methods set forth herein may be administered to the subjectin a once daily extended release solid oral dosage form. In particular,in one embodiment, the methods comprise once daily administration to thesubject of an extended release (e.g., modified release) solid oraldosage form comprising the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or the solid state form of Compound 1, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1. In one aspect, the dosage form sustains release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1 for from about 4 hours to about 24 hoursfollowing entry of the dosage form into a use environment. In oneembodiment, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment. The term “entry into a use environment” refersto contact of the dosage form with gastric fluids of the subject to whomit is administered. As used herein, the term “release rate” refers tothe percentage of the active ingredient (e.g., Compound 1 or a solidstate form of Compound 1) in the dosage form that is released in thegiven time period, and under the specified conditions. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), per dayof Compound 1 freebase equivalent. In one embodiment, the dosage formcomprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of a solid stateform of Compound 1. In one embodiment, the solid state form is FreebaseHydrate Form B. In one embodiment, the solid state form is FreebaseHydrate Form C. In one embodiment, the solid state form is FreebaseAnhydrate Form D. In one embodiment, the solid state form is TartrateHydrate. In one embodiment, the pharmaceutically acceptable polymericcarrier is a release control polymer, as set forth herein.

Thus, in one aspect, the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 hours to about 24 hours. Inone embodiment, the dosage form releases the active ingredient (i.e.,Compound 1 or a solid state form of Compound 1), at a release rate ofnot more than about 25%, or from about 10% to about 25%, or from about15% to about 20%, or about 20% after passage of about 1 hour followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about40%, or from about 20% to about 40%, or from about 25% to about 35%after passage of about 2 hours following entry into the use environment.In one embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 60%, or from about 30% to about 60%,or from about 40% to about 60%, or from about 45% to about 55% afterpassage of about 4 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 70% or from about 40% to about 70%,or from about 55% to about 70% after passage of about 6 hours followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about80% or from about 55% to about 80%, or from about 60% to about 80% afterpassage of about 6 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 80%, or not less than about 50%, ornot less than about 60%, or not less than about 70%, or not less thanabout 75%, or from about 50% to about 80%, or from about 60% to about80%, or from about 65% to about 80% after passage of about 8 hoursfollowing entry into the use environment. In one embodiment, the dosageform releases the active ingredient at a release rate of not less thanabout 55%, or not less than about 60% or not less than about 70%, or notless than about 80%, or not less than about 85%, or from about 55% toabout 90%, or from about 70% to about 90% after passage of about 10hours following entry into the use environment. In one embodiment, thedosage form releases the active ingredient at a release rate of not lessthan about 65%, or not less than about 70%, or not less than about 80%,or not less than about 90%, or from about 65% to about 99%, or fromabout 80% to about 99%, or from about 90% to about 99% after passage ofabout 16 hours following entry into the use environment. In oneembodiment, the dosage form releases the active ingredient at a releaserate of not less than about 70%, or not less than about 80%, or not lessthan about 90%, or from about 70% to 100%, or from about 80% to 100%after passage of about 20 hours following entry into the useenvironment. In one aspect, the dosage form has a release rate of notmore than about 60% after passage of about 4 hours following entry ofthe dosage form into a use environment, from about 50% to about 80%after passage of about 8 hours following entry of the dosage form into ause environment, from about 55% to about 90% after passage of about 10hours following entry of the dosage form into a use environment, andfrom about 70% to 100% after passage of about 20 hours following entryof the dosage form into a use environment.

In one embodiment, the present disclosure is directed to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis, and systemic lupus erythematosus, themethod comprising once daily administration to a subject suffering fromor susceptible to the condition, of an extended release solid oraldosage form comprising about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating a condition selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis,Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nailpsoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata,hidradenitis suppurativa, atopic dermatitis, and systemic lupuserythematosus, the use comprising once daily administration to a subjectsuffering from or susceptible to the condition, of the extended releasesolid oral dosage form, wherein the solid dosage form comprises about7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase, or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In the foregoing methods, in one embodiment, the pharmaceuticallyacceptable polymeric carrier comprises a release control polymer. In oneembodiment, the release control polymer is hydroxypropylmethylcellulose. In one embodiment, the dosage form comprises a pH modifier.In one embodiment, the pH modifier is tartaric acid. In one embodiment,the dosage form comprises from about 10 w/w % to about 35 w/w % tartaricacid. In one embodiment, the dosage form comprises about 10 w/w %tartaric acid. In one embodiment, the dosage form comprises about 20 w/w% tartaric acid. In one embodiment, the dosage form comprises about 30w/w % tartaric acid.

In another embodiment the methods of the present disclosure furthercomprise administering Compound 1 or a solid state form thereof for atleast 8 weeks. In another embodiment, the methods of the presentdisclosure comprise administering Compound 1 or a solid state formthereof for at least 12 weeks.

In another embodiment, the present disclosure relates to the use of asolid state form of Compound 1 for treating a condition as described inthe various embodiments of the present disclosure.

In another embodiment, the present disclosure relates to a solid stateform of Compound 1 for use in treatment of a condition as described inthe various embodiments of the present disclosure.

III. Combination Therapy and Fixed-Dose Combinations

The present disclosure further relates to (i) methods of treatment anduses as previously described that further comprise the administration ofone or more additional therapeutic agents (i.e., combination therapies),and (ii) pharmaceutical compositions as previously described thatfurther comprise one or more additional therapeutic agents (i.e.,fixed-dose combinations). When administered to a subject in combinationwith one or more additional therapeutic agents, the solid state form ofCompound 1 and the additional therapeutic agent(s) can be administeredas separate dosage forms or as a single dosage form comprising the solidstate form of Compound 1 and the additional therapeutic agent(s). Ifadministered as a separate dosage form, the additional therapeutic agentmay be administered either simultaneously with, or sequentially with,the dosage form comprising the solid state form of Compound 1.

For example, the solid state forms of the present disclosure may beadministered in a pharmaceutically acceptable form either alone or incombination with one or more additional agents that modulate a mammalianimmune system or with anti-inflammatory agents. These agents may includebut are not limited to cyclosporin A (e.g., SANDIMMUNE® or NEORAL®,rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin,mycophenolate (e.g., CELLCEPT®), azathioprine (e.g., IMURAN®),daclizumab (e.g., ZENAPAX®), OKT3 (e.g., ORTHOCLONE®), AtGam, aspirin,acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid,metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam,and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). Incertain embodiments, the one or more additional agents are selected fromthe group consisting of aspirin, acetaminophen, aminosalicylate,ciprofloxacin, corticosteroid, cyclosporine, metronidazole, probiotic,tacrolimus, ibuprofen, naproxen, piroxicam, prednisolone, dexamethasone,anti-inflammatory steroid, methotrexate, chloroquine, azathioprine,hydroxychloroquine, penicillamine, sulfasalazine, leflunomide,tocilizumab, anakinra, abatacept, certolizumab pegol, golimumab,vedolizumab, natalizumab, ustekinumab, rituximab, efalizumab, belimumab,etanercept, infliximab, adalimumab, and immune modulator (e.g.,activator) for CD4+CD25+ Treg cells.

Non-limiting examples of therapeutic agents for rheumatoid arthritiswith which a compound of the invention can be combined include thefollowing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF. Compounds of the invention can be combined with antibodies tocell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30,CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligandsincluding CD154 (gp39 or CD40L). Combinations of therapeutic agents mayinterfere at different points in the autoimmune and subsequentinflammatory cascade. Such examples may include TNF antagonists likechimeric, humanized or human TNF antibodies, adalimumab (such as HUMIRA™brand adalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),golimumab such as SIMPONI™ (golimumab), certolizumab pegol such asCIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, etanercept such as p75TNFR1gG(ENBREL™ brand etanercept) or p55TNFR1gG (lenercept), and also TNFαconverting enzyme (TACE) inhibitors; similarly IL-1 inhibitors(Interleukin-1-converting enzyme inhibitors, IL-1RA etc.) may beeffective for the same reason. Other combinations include Interleukin11.

The solid state form may also be combined with nonbiologic DMARDS orother agents, such as methotrexate, 6-mercaptopurine, azathioprinesulphasalazine, mesalamine, olsalazine chloroquinine/hydroxychloroquine,penicillamine aurothiomalate (intramuscular and oral), azathioprine,colchicine, corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeterol), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adenosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signaling by proinflammatory cytokines such as IL-1(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzymeinhibitors, T-cell signalling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, and 6-mercaptopurines. Thesolid state form may also be combined with methotrexate.

Non-limiting examples of therapeutic agents for inflammatory boweldisease (IBD) with which the solid state form can be combined mayinclude (but are not limited to) the following: budesonide; epidermalgrowth factor; corticosteroids; cyclosporin, sulfasalazine;aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies;growth factors; elastase inhibitors; pyridinyl-imidazole compounds;antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16,IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such asCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolatemofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroidssuch as prednisolone; phosphodiesterase inhibitors; adenosine agonists;antithrombotic agents; complement inhibitors; adrenergic agents; agentswhich interfere with signaling by proinflammatory cytokines such as TNFαor IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1β convertingenzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signalinginhibitors such as kinase inhibitors; metalloproteinase inhibitors;sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin convertingenzyme inhibitors; soluble cytokine receptors and derivatives thereof(e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andanti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ).The solid state form may also be combined with methotrexate.

Examples of therapeutic agents for Crohn's disease with which the solidstate form can be combined include the following: TNF antagonists, forexample, anti-TNF antibodies, adalimumab (such as HUMIRA™ brandadalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),certolizumab pegol such as CIMZIA™, golimumab such as SIMPONI™(golimumab), CDP 571, TNFR-Ig constructs, etanercept such as p75TNFRIgG(ENBREL™ brand etanercept) and lenercept such as p55TNFRIgG (Lenercept™)inhibitors and PDE4 inhibitors.

The solid state form can be combined with corticosteroids, for example,budesonide and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; methylprednisolone sodiumsuccinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis (MS)with which the solid state form can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-β1b(BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of the invention can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. The solid state form may also be combined with agents such asmethotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adenosineagonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signaling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ). Examples of therapeutic agents formultiple sclerosis in which a compound of the invention can be combinedto include interferon-β, for example, IFNβ1a and IFNβ1b; copaxone,corticosteroids, caspase inhibitors, for example inhibitors ofcaspase-1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40ligand and CD80.

The solid state form may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis(AS) with which the solid state form can be combined include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Ig constructs,etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) and lenerceptsuch as p55TNFRIgG (LENERCEPT™).

Non-limiting examples of therapeutic agents for psoriasis (Ps, such asmoderate to severe plaque psoriasis) with which the solid state form canbe combined include the following: calcipotriene, clobetasol propionate,triamcinolone acetonide, halobetasol propionate, tazarotene,methotrexate, fluocinonide, betamethasone diprop augmented, fluocinoloneacetonide, acitretin, tar shampoo, betamethasone valerate, mometasonefuroate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,fluticasone propionate, azithromycin, hydrocortisone, moisturizingformula, folic acid, desonide, pimecrolimus, coal tar, diflorasonediacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuthsubgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen,halcinonide, salicylic acid, anthralin, clocortolone pivalate, coalextract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur,desoximetasone, diazepam, emollient, fluocinonide/emollient, mineraloil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropylmyristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boricacid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab,tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874,ustekinumab, and adalimumab (such as HUMIRA™ brand adalimumab).

Non-limiting examples of therapeutic agents for psoriatic arthritis(PsA) with which the solid state form can be combined include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, adalimumab (such asHUMIRA™ brand adalimumab), and efalizumab.

Examples of therapeutic agents for SLE (Lupus) with which the solidstate form can be combined include the following: NSAIDS, for example,diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budesonide, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample CELLCEPT®. The solid state form may also be combined with agentssuch as sulfasalazine, 5-aminosalicylic acid, olsalazine, IMURAN® andagents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-1ra. The solid state formmay also be used with T cell signaling inhibitors, for example, tyrosinekinase inhibitors; or molecules that target T cell activation molecules,for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 familyantibodies. The solid state form can be combined with IL-11 oranti-cytokine antibodies, for example, fontolizumab (anti-IFNgantibody), or anti-receptor receptor antibodies, for example, anti-IL-6receptor antibody and antibodies to B-cell surface molecules. The solidstate form may also be used with UP 394 (abetimus), agents that depleteor inactivate B-cells, for example, Rituximab (anti-CD20 antibody),lymphostat-B (anti-BlyS antibody), TNF antagonists, for example,anti-TNF antibodies, adalimumab (such as HUMIRA™ brand adalimumab),infliximab such as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Igconstructs, etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) andlenercept such as p55TNFRIgG (LENERCEPT™).

The solid state form may also be combined with an immune modulator forCD4+CD25+ Treg cells. Treg cells are essential for maintaining normalimmune homeostasis. In patients with autoimmune diseases, reducednumbers or functional impairment of Treg cells has been observed,leading to loss of this finely-tuned mechanism. A humanized agonisticmonoclonal antibody, BT-061, binds to a unique epitope of human CD4, andinduces Treg-specific signaling events that lead to their functionalactivation. Pre-clinical data using isolated Treg cells and rheumatoidarthritis synovial fluid indicate that BT-061 leads to suppression ofCD4+ and CD8+T effector cell proliferation, reduction of the expressionof pro-inflammatory cytokines, and increase in the production of theanti-inflammatory cytokine TGFβ. Thus similar immune modulators forCD4+CD25+ Treg cells can also be co-administered with a compound of theinvention for treating any of the inflammatory disease/disorder, or anautoimmune disease/disorder described herein, including but not limitedto rheumatoid arthritis, Crohn's disease, ankylosing spondylitis,psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupuserythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome,Sjogren's syndrome, alopecia areata, vitiligo, or atopic dermatitis. Incertain embodiments, the combination treats rheumatoid arthritis,Crohn's disease, psoriasis, or psoriatic arthritis, including moderatelyto severely active rheumatoid arthritis, Crohn's disease, psoriasis, orpsoriatic arthritis. In certain embodiments, the rheumatoid arthritis,Crohn's disease, psoriasis, or psoriatic arthritis patient being treatedhas inadequately responded to or has discontinued therapy due to loss ofresponse to or intolerance to a first line therapy (such as a DMARD,including methotrexate) or an anti-TNFα therapy.

In certain embodiments, the immune modulator has one or more (or all) ofthe following properties: (1) activates a subset of CD4+ T cellscomprising CD4+CD25+ regulatory T cells (Treg), or CD4+CD25+ Treg cells;(2) binds only to a special epitope of the human CD4 antigen (such asthe IgG-like C2 type 1 domain of CD4), which said epitope of human CD4may be bound by a mouse IgG1 anti-CD4 monoclonal antibody B-F5 or ahumanized version thereof, such as the BT-061 hB-F5 antibodytregalizumab as described in U.S. Pat. No. 7,452,981 (incorporatedherein by reference, including all sequences of the VH and VL chainsdisclosed therein); (3) provides an activation signal to naturallyoccurring Treg cells but does not activate conventional T cells (e.g.,CD4+ T cells that are not activated in (1), CD8+ cytotoxic T cells,etc.); and (4) is not a depleting anti-CD4 antibody that depletes CD4+ Tcells, and/or does not appreciably trigger ADCC or CDC.

IV. Pharmaceutical Compositions

The present disclosure further relates, in part, to compositionscomprising Compound 1 or a pharmaceutically acceptable salt thereof, orone or more solid state forms of Compound 1. Although the solid stateform may be administered alone or in the form of a pharmaceuticalcomposition, administration generally will be in the form of apharmaceutical composition. In some embodiments, the compositioncomprises Compound 1 or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in association with a pharmaceuticallyacceptable carrier. The preferred composition depends on the method ofadministration, and typically comprises one or more conventionalpharmaceutically acceptable carriers, adjuvants, and/or vehicles(together referred to as “excipients”). Such compositions can beformulated for various routes of systemic or local delivery for example,by oral administration, topical administration, transmucosaladministration, rectal administration, intravaginal administration, oradministration by subcutaneous, intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the compounds or salts are ordinarily combined with one or moreexcipients. If administered per os, the compounds or salts can be mixedwith, for example, lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise pH modifiers, such as sodium citrate; magnesium orcalcium carbonate or bicarbonate; tartaric acid, fumaric acid, citricacid, succinic acid, malic acid, and phosphoric acid and combinationsthereof. Tablets and pills additionally can be prepared with entericcoatings.

In one embodiment, the pharmaceutical composition is a tablet dosageform. In one aspect, the tablet is coated with a pharmaceuticallyacceptable polymer.

In one embodiment, tablet is a controlled-release formulation, such asan extended release tablet dosage form (also referred to herein as amodified release or sustained release formulation). Such formulationspermit the sustained release of the active ingredient over an extendedperiod of time, as compared to immediate release solid dosage forms,which permit the release of most or all of the active ingredient over ashort period of time (e.g., typically around 60 minutes or less). In oneaspect, the tablet comprises an active ingredient and at least oneadditive selected from the group consisting of a release controlpolymer, a filler, a glidant, a lubricant (e.g., for use in compactingthe granules), a pH modifier, a surfactant, and combinations thereof. Inone aspect, the tablet comprises an active ingredient, a release controlpolymer, a filler, a glidant, and a lubricant. In one aspect, the tabletcomprises an active ingredient, a release control polymer, a filler, aglidant, a lubricant, and a pH modifier.

In certain embodiments, the release control polymer will be ahydrophilic polymer. Examples of suitable release control polymersinclude, but are not limited to a cellulose derivative with a viscosityof between 1000 and 150,000 mPA-s, hydroxypropylmethyl cellulose (e.g.,Hypromellose 2208 or controlled release grades of hydroxypropylmethylcellulose, including the E, F, and K series), copolymers of acrylic acidcrosslinked with a polyalkenyl polyether (e.g., Carbopol® polymers),hydroxypropyl cellulose, hydroxyethyl cellulose, non-ionic homopolymersof ethylene oxide (e.g., Polyox™), water soluble natural gums ofpolysaccharides (e.g., xanthan gum, alginate, locust bean gum, etc.),crosslinked starch, polyvinyl acetates, polyvinylpyrrolidone, mixturesof polyvinyl acetates and polyvinyl pyrrolidone, and combinationsthereof. In one embodiment, the release control polymer is selected fromthe group consisting of hydroxypropylmethyl cellulose, copolymers ofacrylic acid crosslinked with a polyalkenyl polyether (e.g., Carbopol®polymers), and combinations thereof. Examples of suitable fillers(“bulking agents”) include, but are not limited to, microcrystallinecellulose (e.g., Avicel® PH 101; Avicel® PH 102), mannitol (e.g.,Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, andthe like. In one embodiment, the filler is selected from the groupconsisting of microcrystalline cellulose, mannitol, and combinationsthereof. Examples of suitable glidants include, but are not limited to,silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate,magnesium silicate, talc, and combinations thereof. In one embodiment,the glidant is colloidal silicone dioxide. Examples of suitablelubricants include, but are not limited to, polyethylene glycol (e.g.,having a molecular weight of from 1000 to 6000), magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, and the like. In oneembodiment, the lubricant is magnesium stearate. Examples of suitable pHmodifiers include, but are not limited to, organic acids, such astartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate;magnesium or calcium carbonate or bicarbonate; and combinations thereof.In one embodiment, the pH modifier is tartaric acid. Examples ofsuitable surfactants include sodium lauryl sulfate.

In one embodiment, the pharmaceutical composition comprises from about10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaricacid, fumaric acid, citric acid, succinic acid, malic acid, orcombinations thereof. In other embodiments, the formulation comprisesfrom about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %,about 15 w/w %, about 20 w/w %, about 25 w/w % or about 30 w/w % pHmodifier. In one embodiment, the pH modifier is tartaric acid.

V. Pharmacokinetic Parameters

15 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) Compound 1(freebase), or a pharmaceutically acceptable salt thereof, or acrystalline hydrate of Compound 1 in an amount sufficient to deliver tothe subject 15 mg of Compound 1 freebase equivalent. In one embodiment,the freebase or the hydrate is in a once daily extended releaseformulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 15 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 15mg doses to achieve a steady-state. By a single 15 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 15 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

30 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) 30 mg ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora crystalline hydrate of Compound 1 in an amount sufficient to deliverto the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the freebase or the hydrate is in a once daily extendedrelease formulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 30 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 30mg doses to achieve a steady-state. By a single 30 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

Extended Release Tablets

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate used in the methodsof the present disclosure is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isin a once daily extended release formulation, and the formulationdelivers about 7.5 mg or about 15 mg or about 30 mg or about 45 mg perunit dosage form (e.g., per tablet or capsule) of Compound 1 (freebaseequivalent) orally QD (once daily). In one particular embodiment, thecrystalline hydrate is Freebase Hydrate Form C.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 7.5 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 3 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 15 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 6 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 30 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 12 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 45 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 18 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

VI. Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a chronic, inflammatory rheumatic diseaseprimarily affecting the axial skeleton, characterized by chronic backpain (including nocturnal back pain), morning stiffness, enthesitis,peripheral arthritis, and extra-articular manifestations. The “early”form of this disease (non-radiographic axial spondyloarthritis(nr-axSpA)) shares many of AS disease characteristics.

Due to the longstanding debilitating nature of AS, irreversiblestructural damage often occurs, negatively impacting patients' lives. Nocure for AS exists, thus the primary goal of treatment is to maximizepatients' quality of life through controlling the signs and symptoms ofdisease, preventing structural damage, and maintaining physicalfunction, ideally by achieving sustained clinical remission or, atminimum, low disease activity. Nonsteroidal anti-inflammatory drugs(NSAIDs) are the first-line treatment for AS, followed by biologicdisease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosisfactor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, inpatients who do not sufficiently respond to NSAIDs. TNF inhibitors andIL-17 inhibitors are efficacious in some patients with AS, but there arestill patients for whom neither of these approved therapies addressindividual treatment goals. AS is a difficult disease to treat, as shownbased on low efficacy achieved with IL-6 inhibitors tocilizumab andsarilumab, as well as IL-12/23 inhibitor ustekinumab and T cell blockadeinhibitor abatacept. See, e.g., Sieper et al., Ann. Rheum. Dis. 201473:95-100, Sieper et al., Ann. Rheum. Dis. 2015 74:1051-1057; Deodhar etal., Arthritis and Rheumatology 2019 71:258-270, and Song et al., Ann.Rheum. Dis. 2011 70:1108-1110.

The JAK family is composed of 4 members: JAK1, 2, 3, and tyrosine kinase2 (Tyk2). These cytoplasmic tyrosine kinases act in tandem to activatethe Signal Transducer and Activator of Transcription (STAT) thattransduce cytokine-mediated signals and are associated with multiplemembrane cytokine receptors such as common gamma-chain (CGC) receptorsand the glycoprotein 130 trans-membrane proteins. JAK3 and JAK1 arecomponents of the CGC cytokine receptor complexes that are responsiblefor the signaling of the inflammatory cytokines IL-2, -4, -7, -9, -15and −21; whereas IL-12 and IL-23 signal through JAK2 and Tyk2. SeeGhoreschi, et al., Immunol Rev. (2009), 228:273-87. Propagation of thesesignals is important in the amplification of inflammatory responses inaxial spondyloarthritis (axSpA). Upadacitinib, a JAK inhibitorengineered for increased selectivity for JAK1 over JAK2, JAK3, andtyrosine kinase 2, has been investigated for the treatment ofbDMARD-naïve patients with AS who had an inadequate response tonon-steroidal anti-inflammatory drugs (NSAIDs) in the randomized,placebo-controlled phase 2/3 SELECT-AXIS 1 study. See Example 31,herein. A second study (SELECT-AXIS-2) expanded the scope of enrollmentto non-radiographic axial spondyloarthritis (nr-axSpA) patients and ASbDMARD-IR patients. See Examples 32 and 33 herein.

The SELECT-AXIS 1 met its primary endpoint of significantly greaterachievement of Assessment of SpondyloArthritis International Society(ASAS40) response at Week 14, as well as several disease activitymeasures (ASDAS, BASDAI, ASAS, and their components), inflammation(based on MRI of spine and sacroiliac joints as well as hsCRP), physicalfunction (BASFI), quality of life (ASQoL, ASAS HI), and other aspects ofdisease (BASMI, MASES), reflecting significant improvement in outcomesfor upadacitinib versus placebo. Furthermore, a review of the placebocorrected data for upadacitinib at Week 14, biologics Ixekizumab andAdalimumab at Week 16, and JAK small molecule inhibitors Tofacitinib andFilgotinib at Week 12 for key primary and secondary endpoints, while nota head to head comparison, suggests that upadacitinib 15 mg QD showsdecided promise for the more difficult to achieve endpoints ASAS PR,ASDAS ID, and ASDAS LDA versus the other two JAK small moleculeinhibitors, with a remarkable efficacy only comparable to thatdemonstrated with the biologics. See U.S. Pat. App. No. 2021/0228575(Example 2), and van der Heijde et al. Lancet (2018) 392: 2441-2451, vander Heijde D, et al. Ann. Rheum. Dis. (2017) 1-8; van der Heijde et al.Lancet (2018) 2378-2387. Furthermore, this efficacy, once achieved atWeek 14, was sustained or improved over time, with long term efficacy inthese difficult to achieve endpoints (including ASDAS major improvement(MI) and ASDAS clinically important improvement (CII)), sustained orimproved up to and including Week 64. In patients who switched fromplacebo to upadacitinib at Week 14, a similar speed of onset andmagnitude of efficacy response was observed up to and including Week 64compared with those who received continuous upadacitinib starting atWeek 0. Based on the results of phase 2/3 study SELECT-AXIS 1 and theconsistent safety data from other upadacitinib clinical trials, thebenefit-risk profile of upadacitinib in AS (particularly compared to therisk profile of other small molecule JAK inhibitors), and viewed in thecontext of the benefit-risk of TNF inhibitors and IL-17 inhibitors,presents a promising oral targeted treatment option for patients withAS, especially for those AS (as well as nr-axSpA patients) who haveactive disease and inadequate response to NSAIDs.

In one embodiment, the JAK1 inhibitor useful in the methods disclosedherein is upadacitinib freebase. Upadacitinib freebase solid state formsinclude amorphous upadacitinib freebase and crystalline freebases ofupadacitinib. Crystalline freebases of upadacitinib include thoseselected from the group consisting of crystalline freebase solvates ofupadacitinib, crystalline freebase hydrates of upadacitinib (e.g.,crystalline freebase hemihydrates of upadacitinib), and crystallinefreebase anhydrates of upadacitinib. In one embodiment, the crystallinefreebase of upadacitinib is a crystalline freebase hemihydrate ofupadacitinib. In one embodiment, the crystalline freebase ofupadacitinib is Upadacitinib Freebase Hydrate Form C (which is ahemihydrate) as described in WO 2018/165581 and WO 2017/066775. Otherspecific examples of solid state forms of the JAK1 inhibitor suitablefor use in the methods disclosed herein include those selected from thegroup consisting of Amorphous Upadacitinib Freebase, UpadacitinibFreebase Solvate Form A, Upadacitinib Freebase Hydrate Form B,Upadacitinib Freebase Anhydrate Form D, and Upadacitinib TartrateHydrate, each as described in WO 2018/165581 and WO 2017/066775.

VII. Methods of Treating Ankylosing Spondylitis (AS)

Further provided are methods of treating ankylosing spondylitis (AS).For example, in one aspect, provided is a method of treating AS,including active AS, comprising administering orally once a day a doseof the JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals. In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

Disease activity/severity for AS may be measured using a variety ofindexes, including those set forth herein for the treatment of axSpA. Inone particular aspect, provided is a method of treating AS, includingactive AS, comprising administering a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein the subject achieves an Assessment ofSpondyloArthritis International Society 40 (ASAS40) response followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the subject isbDMARD naïve. In one aspect, the subject is bDMARD-IR. In one aspect,the subject is an adult.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, the subject achieves an ASAS40 response within 2weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within16 weeks, within 18 weeks, within 20 weeks, within 24 weeks, within 32weeks, within 40 weeks, within 52 weeks, within 64 weeks, within 76weeks, within 88 weeks, within 96 weeks, within 104 weeks, and/or within152 weeks (including at week 2, week 4, week 8, week 12, week 14, week16, week 18, week 20, week 24, week 32, week 40, week 52, week 64, week76, week 88, week 96, week 104, and/or week 152) of administration ofthe first dose of the JAK1 inhibitor. In one aspect, the subjectachieves an ASAS 40 response within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), and the ASAS40response is maintained or improved until at least 64 weeks afteradministration of the first dose (e.g., up to and including week 64). Inone embodiment, the subject achieves an ASAS 40 response within 2 weeksof administration of the first dose (including at week 2), and maintainsor improves the ASAS40 response until at least 14 weeks afteradministration of the first dose (e.g., until at least week 14). In oneembodiment, the subject achieves an ASAS 40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2), and the ASAS40 response is maintained or improved until atleast 64 weeks after administration of the first dose (e.g., up to andincluding week 64). In one aspect, the subject achieves an ASAS 40response within 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14), and the ASAS40 response is maintainedor improved until at least 104 weeks after administration of the firstdose (e.g., up to and including week 104). In one aspect, the subjectachieves an ASAS 40 response within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), and the ASAS40response is maintained or improved until at least 152 weeks afteradministration of the first dose (e.g., up to and including week 152).In one embodiment, the subject achieves an ASAS 40 response within 4weeks of administration of the first dose (including at week 4), andmaintains or improves the ASAS40 response until at least 14 weeks afteradministration of the first dose (e.g., until at least week 14). In oneembodiment, the subject achieves an ASAS 40 response within 4 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 4), and the ASAS40 response is maintained or improved until atleast 64 weeks after administration of the first dose (e.g., up to andincluding week 64). In one embodiment, the subject achieves an ASAS 40response within 4 weeks of administration of the first dose of the JAK1inhibitor (including at week 4), and the ASAS40 response is maintainedor improved until at least 104 weeks after administration of the firstdose (e.g., up to and including week 104). In one embodiment, thesubject achieves an ASAS 40 response within 4 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 4), and theASAS40 response is maintained or improved until at least 152 weeks afteradministration of the first dose (e.g., up to and including week 152).

In one aspect, the subject alternately or additionally achieves within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14) at least one additional result selected from thegroup consisting of: ASAS partial remission (PR); BASDAI50 response;change (improvement) from baseline in MRI SPARCC score for spine(MRI-Spine SPARCC); change (improvement) from baseline in ASDAS; change(improvement) from baseline in BASFI; ASDAS low disease activity (LDA);ASDAS inactive disease (ID); ASDAS major improvement (MI); and ASDASclinically important improvement (CII). In one aspect, the subjectalternately or additionally achieves within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14) at leastone additional result selected from the group consisting of: change(improvement) from baseline in ASDAS (e.g., ASDAS CRP); change(improvement) from baseline in MRI SPARCC score for spine (MRI-SpineSPARCC); BASDAI50 response; ASAS20 response; ASDAS inactive disease(ID); change (improvement) from baseline in Patient's Assessment ofTotal Back Pain (Total Back Pain score); change (improvement) frombaseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal BackPain score); ASDAS low disease activity (LDA); (change (improvement)from baseline in BASFI; ASAS partial remission (PR); change(improvement) from Baseline in Ankylosing Spondylitis Quality of Life(ASQoL); change (improvement) from baseline in ASAS Health Index (HI);change (improvement) from baseline in Linear Bath Ankylosing SpondylitisMetrology Index (BASMIlin) (Mobility); and change (improvement) frombaseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)(Enthesitis). In one aspect, the subject achieves the result within 14weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the result is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the JAK1 inhibitor is upadacitinib freebase. In oneaspect, the JAK1 inhibitor is administered in an amount sufficient todeliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 2 weeks,for at least 4 weeks, for at least 8 weeks, for at least 12 weeks, forat least 14 weeks, for at least 16 weeks, for at least 18 weeks, for atleast 20 weeks, for at least 24 weeks, for at least 32 weeks, for atleast 40 weeks, for at least 52 weeks, for at least 64 weeks, for atleast 76 weeks, for at least 88 weeks, for at least 96 weeks, for atleast 104 weeks, and/or for at least 152 weeks. In one embodiment, theJAK1 inhibitor is administered orally once a day for at least 14 weeks.In one aspect, provided is a method of treating AS, including active AS,in a population of subjects in need thereof, the method comprisingadministering a dose of the JAK1 inhibitor to the subjects in certainamounts and/or at certain intervals as described herein, wherein aportion of subjects in the treated population (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 44%, or at least 45% of the subjectsin the treated population) achieve an ASAS40 response followingadministration of the JAK1 inhibitor. In one aspect, subjects in thetreated population achieve an ASAS40 response within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, subjects in the treated population achieve anASAS40 response within 14 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 14), and the response ismaintained or improved after week 14 by continuing to administer a dailydose of the JAK1 inhibitor. In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 4 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 4). In oneaspect, subjects in the treated population of the subjects achieve anASAS40 response within 4 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 4), and the response is maintainedor improved after week 4 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve an ASAS40 response within 2 weeks, within 4 weeks, within 8weeks, within 12 weeks, within 14 weeks, within 16 weeks, within 18weeks, within 20 weeks, within 24 weeks, within 32 weeks, within 40weeks, within 52 weeks, within 64 weeks, within 76 weeks, within 88weeks, within 96 weeks, within 104 weeks, and/or within 152 weeks(including at week 2, week 4, week 8, week 12, week 14, week 16, week18, week 20, week 24, week 32, week 40, week 52, week 64, week 76, week88, week 96, week 104, and/or week 152) of administration of the firstdose of the JAK1 inhibitor. In one embodiment, subjects in the treatedpopulation achieve an ASAS 40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theASAS40 response is maintained or improved until at least 64 weeks, atleast 104 weeks, and/or at least 152 weeks after administration of thefirst dose (e.g., up to and including week 64, week 104, and/or week152). In one embodiment, subjects in the treated population achieve anASAS 40 response within 4 weeks of administration of the first dose(including at week 4), and maintains or improves the ASAS40 responseuntil at least 14 weeks after administration of the first dose (e.g.,until at least week 14). In one aspect, subjects in the treatedpopulation alternately or additionally achieve within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14) at least one additional result selected from the groupconsisting of: change (improvement) from baseline in ASDAS (e.g., ASDASCRP); change (improvement) from baseline in MRI SPARCC score for spine(MRI-Spine SPARCC); BASDAI50 response; ASAS20 response; ASDAS inactivedisease (ID); change (improvement) from baseline in Patient's Assessmentof Total Back Pain (Total Back Pain score); change (improvement) frombaseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal BackPain score); ASDAS low disease activity (LDA); (change (improvement)from baseline in BASFI; ASAS partial remission (PR); change(improvement) from Baseline in Ankylosing Spondylitis Quality of Life(ASQoL); change (improvement) from baseline in ASAS Health Index (HI);change (improvement) from baseline in Linear Bath Ankylosing SpondylitisMetrology Index (BASMIlin) (Mobility); and change (improvement) frombaseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)(Enthesitis). In one aspect, subjects in the treated population achievethe result within 14 weeks of administration of the first dose of theJAK1 inhibitor (including at week 14), and the result is maintained orimproved after week 14 by continuing to administer a daily dose of theJAK1 inhibitor. In certain embodiments, for any of the aforementionedresults achieved, a statistically significant population of the subjectsin the treated population, and/or at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least44%, or at least 45% of the subjects in the treated population, achievethe result. In one aspect, the JAK1 inhibitor is upadacitinib freebase.In one aspect, a dose of the JAK1 inhibitor is administered to thepopulation in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredto the population orally once a day for at least 14 weeks. In oneaspect, the subjects in the population are bDMARD-IR.

Further provided are methods of treating AS, including active AS, in asubject in need thereof, comprising administering orally once a day adose of a JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals as described herein, wherein the subjectachieves ASAS partial remission (PR), ASDAS low disease activity (LDA),ASDAS inactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) following administration of theJAK1 inhibitor. In one embodiment, the subject achieves ASAS PR, ASDASLDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14). In one embodiment, the subject achieves each result (e.g.,ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and ASDAS CII) within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves ASAS PR, ASDAS LDA, ASDASID, ASDAS MI, and/or ASDAS CII within 2 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 2). In one aspect,the subject achieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/orASDAS CII within 2 weeks, within 4 weeks, within 8 weeks, within 12weeks, within 14 weeks, within 16 weeks, within 18 weeks, within 20weeks, within 24 weeks, within 32 weeks, within 40 weeks, within 52weeks, within 64 weeks, within 76 weeks, within 88 weeks, within 96weeks, and/or within 104 weeks (including at week 2, week 4, week 8,week 12, week 14, week 16, week 18, week 20, week 24, week 32, week 40,week 52, week 64, week 76, week 88, week 96, and/or week 104) ofadministration of the first dose of the JAK1 inhibitor. In one aspect,the subject achieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/orASDAS CII within 14 weeks of administration of the first dose of theJAK1 inhibitor (including at week 14), and the response is maintained orimproved after week 14 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, the subject achieves ASAS PR, ASDAS LDA,ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 2), and theresponse is maintained or improved after week 2 by continuing toadminister the daily dose of the JAK1 inhibitor. In one aspect, the JAK1inhibitor is upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 2 weeks, for at least 4 weeks, for atleast 8 weeks, for at least 12 weeks, for at least 14 weeks, for atleast 16 weeks, for at least 18 weeks, for at least 20 weeks, for atleast 24 weeks, for at least 32 weeks, for at least 40 weeks, for atleast 52 weeks, for at least 64 weeks, for at least 76 weeks, for atleast 88 weeks, for at least 96 weeks, and/or for at least 104 weeks. Inone embodiment, the JAK1 inhibitor is administered orally once a day forat least 14 weeks. In one aspect, the subject is bDMARD naïve. In oneaspect, the subject is bDMARD-IR. In one aspect, the subject is anadult.

Further provided are methods of treating AS, including active AS, in apopulation of subjects in need thereof, the method comprisingadministering orally once a day a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein a portion of the subjects in the treatedpopulation (e.g., a statistically significant population of subjects inthe treated population, and/or at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 44% orat least 45% of the subjects in the treated population) achieve change(improvement) from baseline in ASDAS (e.g., ASDAS CRP); change(improvement) from baseline in MRI SPARCC score for spine (MRI-SpineSPARCC); BASDAI50 response; ASAS20 response; ASDAS inactive disease(ID); change (improvement) from baseline in Patient's Assessment ofTotal Back Pain (Total Back Pain score); change (improvement) frombaseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal BackPain score); ASDAS low disease activity (LDA); (change (improvement)from baseline in BASFI; ASAS partial remission (PR); change(improvement) from Baseline in Ankylosing Spondylitis Quality of Life(ASQoL); change (improvement) from baseline in ASAS Health Index (HI);change (improvement) from baseline in Linear Bath Ankylosing SpondylitisMetrology Index (BASMIlin) (Mobility); and/or change (improvement) frombaseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)(Enthesitis) following administration of the JAK1 inhibitor. In oneaspect, subjects in the treated population achieve any one or more ofthe aforementioned results within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14). In one aspect,subjects in the treated population achieve each result within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, subjects in the treated population achieve anyone or more of the aforementioned results within 4 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 4). In one aspect, subjects in the treated population achieve anyone or more of the aforementioned results within 2 weeks, within 4weeks, within 8 weeks, within 12 weeks, within 14 weeks, within 16weeks, within 18 weeks, within 20 weeks, within 24 weeks, within 32weeks, within 40 weeks, within 52 weeks, within 64 weeks, within 76weeks, within 88 weeks, within 96 weeks, within 104 weeks, and/or within152 weeks (including at week 2, week 4, week 8, week 12, week 14, week16, week 18, week 20, week 24, week 32, week 40, week 52, week 64, week76, week 88, week 96, week 104, and/or week 152) of administration ofthe first dose of the JAK1 inhibitor. In one aspect, subjects in thetreated population achieve any one or more of the aforementioned resultswithin 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14), and the response is maintained orimproved after week 14 by continuing to administer the daily dose of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve any one or more of the aforementioned results within 4 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 4), and the response is maintained or improved after week 4 bycontinuing to administer the daily dose of the JAK1 inhibitor. Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 44%, or at least45% of the subjects in the treated population, achieve the result. Inone aspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect,the JAK1 inhibitor is administered in an amount sufficient to deliver 15mg of upadacitinib freebase equivalent. In one aspect, the JAK1inhibitor is administered orally once a day for at least 2 weeks, for atleast 4 weeks, for at least 8 weeks, for at least 12 weeks, for at least14 weeks, for at least 16 weeks, for at least 18 weeks, for at least 20weeks, for at least 24 weeks, for at least 32 weeks, for at least 40weeks, for at least 52 weeks, for at least 64 weeks, for at least 76weeks, for at least 88 weeks, for at least 96 weeks, for at least 104weeks, and/or for at least 152 weeks. In one embodiment, the JAK1inhibitor is administered orally once a day for at least 14 weeks

In one aspect, provided is a method of treating AS, including active AS,in a population of subjects in need thereof, the method comprisingadministering a dose of the JAK1 inhibitor to the subjects in certainamounts and/or at certain intervals as described herein, wherein aportion of subjects in the treated population (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation) achieve an ASAS40 response following administration of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve an ASAS40 response within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14). In one aspect,subjects in the treated population achieve an ASAS40 response within 14weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, subjects in the treated population achieve an ASAS40response within 2 weeks of administration of the first dose of the JAK1inhibitor (including at week 2). In one aspect, subjects in the treatedpopulation of the subjects achieve an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, subjects in the treated population achieve an ASAS40 responsewithin 2 weeks, within 4 weeks, within 8 weeks, within 12 weeks, within14 weeks, within 16 weeks, within 18 weeks, within 20 weeks, within 24weeks, within 32 weeks, within 40 weeks, within 52 weeks, within 64weeks, within 76 weeks, within 88 weeks, within 96 weeks, and/or within104 weeks (including at week 2, week 4, week 8, week 12, week 14, week16, week 18, week 20, week 24, week 32, week 40, week 52, week 64, week76, week 88, week 96, and/or week 104) of administration of the firstdose of the JAK1 inhibitor. In one embodiment, subjects in the treatedpopulation achieve an ASAS 40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theASAS40 response is maintained or improved until at least 64 weeks afteradministration of the first dose (e.g., up to and including week 64). Inone embodiment, subjects in the treated population achieve an ASAS 40response within 2 weeks of administration of the first dose (includingat week 2), and maintains or improves the ASAS40 response until at least14 weeks after administration of the first dose (e.g., until at leastweek 14). In one aspect, subjects in the treated population alternatelyor additionally achieve within 14 weeks of administration of the firstdose of the JAK1 inhibitor (including at week 14) at least oneadditional result selected from the group consisting of: ASAS partialremission (PR); BASDAI50 response; change (improvement) from baseline inMRI SPARCC score for spine (MRI-Spine SPARCC); change (improvement) frombaseline in ASDAS; change (improvement) from baseline in BASFI; ASDASlow disease activity (LDA); ASDAS inactive disease (ID); ASDAS majorimprovement (MI); and ASDAS clinically important improvement (CII). Inone aspect, subjects in the treated population achieve the result within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the result is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In certain embodiments, for any of the aforementioned results achieved,a statistically significant population of the subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, a dose ofthe JAK1 inhibitor is administered to the population in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered to the population orally oncea day for at least 14 weeks. In one aspect, the subjects in thepopulation are bDMARD naïve. In one aspect, the subjects in thepopulation are bDMARD-IR.

Further provided are methods of treating AS, including active AS, in apopulation of subjects in need thereof, the method comprisingadministering orally once a day a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein a portion of the subjects in the treatedpopulation (e.g., a statistically significant population of subjects inthe treated population, and/or at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population) achieve ASAS partialremission (PR), ASDAS low disease activity (LDA), ASDAS inactive disease(ID), ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) following administration of the JAK1 inhibitor. In oneaspect, subjects in the treated population achieve ASAS PR, ASDAS LDA,ASDAS ID, ASDAS MI, and/or ASDAS CII within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14). In oneaspect, subjects in the treated population achieve each result (e.g.,ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and ASDAS CII) within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, subjects in the treated population achieve ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, subjects in the treated population achieve ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within16 weeks, within 18 weeks, within 20 weeks, within 24 weeks, within 32weeks, within 40 weeks, within 52 weeks, within 64 weeks, within 76weeks, within 88 weeks, within 96 weeks, and/or within 104 weeks(including at week 2, week 4, week 8, week 12, week 14, week 16, week18, week 20, week 24, week 32, week 40, week 52, week 64, week 76, week88, week 96, and/or week 104) of administration of the first dose of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer the daily dose of the JAK1inhibitor. In one aspect, subjects in the treated population achieveASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer the daily dose of the JAK1 inhibitor. Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 2 weeks, for at least 4weeks, for at least 8 weeks, for at least 12 weeks, for at least 14weeks, for at least 16 weeks, for at least 18 weeks, for at least 20weeks, for at least 24 weeks, for at least 32 weeks, for at least 40weeks, for at least 52 weeks, for at least 64 weeks, for at least 76weeks, for at least 88 weeks, for at least 96 weeks, and/or for at least104 weeks. In one embodiment, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subjects in thepopulation are bDMARD naïve. In one aspect, the subjects in thepopulation are bDMARD-IR. In one aspect, the subjects are adults.

Further provided are methods of reducing the signs and symptoms of AS.In one aspect, provided is a method of reducing the signs and symptomsof AS, including active AS, the method comprising administering a doseof the JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals. In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

In one aspect of a method of reducing the signs and symptoms of AS,including active AS, wherein the subject achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), at least one result selected from the group consisting of: anASAS40 response; a change (improvement) from baseline in ASDAS; a change(improvement) from baseline in MRI-Spine SPARCC; ASAS partial remission(PR); a BASDAI50 response; a change (improvement) from baseline inBASFI; a change (improvement) from baseline in ASQoL; a change(improvement) from baseline in ASAS Health Index (HI); a change(improvement) from baseline in MASES (enthesitis); a change(improvement) from baseline in BASMI_(lin) (mobility); and a change(improvement) from baseline in WPAI-Axial SpA. In certain embodiments,for any of the aforementioned results achieved, a statisticallysignificant population of the subjects in the treated population, and/orat least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation, achieve the result. In certain embodiments, for any of theaforementioned results achieved, the subject (or subjects in the treatedpopulation) achieve the result or results within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result (or results) is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of a method of reducing the signs and symptoms of AS,including active AS, wherein the subject achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), at least one result selected from the group consisting of: anASAS40 response; change (improvement) from baseline in ASDAS (e.g.,ASDAS CRP); change (improvement) from baseline in MRI SPARCC score forspine (MRI-Spine SPARCC); BASDAI50 response; ASAS20 response; ASDASinactive disease (ID); change (improvement) from baseline in Patient'sAssessment of Total Back Pain (Total Back Pain score); change(improvement) from baseline in Patient's Assessment of Nocturnal BackPain (Nocturnal Back Pain score); ASDAS low disease activity (LDA);(change (improvement) from baseline in BASFI; ASAS partial remission(PR); change (improvement) from Baseline in Ankylosing SpondylitisQuality of Life (ASQoL); change (improvement) from baseline in ASASHealth Index (HI); change (improvement) from baseline in Linear BathAnkylosing Spondylitis Metrology Index (BASMI_(lin)) (Mobility); and/orchange (improvement) from baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES) (Enthesitis). In certain embodiments, for anyof the aforementioned results achieved, a statistically significantpopulation of the subjects in the treated population, and/or at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 44%, or at least 45% of the subjects in thetreated population, achieve the result. In certain embodiments, for anyof the aforementioned results achieved, the subject (or subjects in thetreated population) achieve the result or results within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result (or results) is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of a method of reducing the signs and symptoms of AS,including active AS, wherein the subject achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), at least one result selected from the group consisting of: anASAS40 response; change (improvement) from baseline in ASDAS (e.g.,ASDAS CRP); change (improvement) from baseline in MRI SPARCC score forspine (MRI-Spine SPARCC); BASDAI50 response; ASAS20 response; ASDASinactive disease (ID); change (improvement) from baseline in Patient'sAssessment of Total Back Pain (Total Back Pain score); change(improvement) from baseline in Patient's Assessment of Nocturnal BackPain (Nocturnal Back Pain score); ASDAS low disease activity (LDA);(change (improvement) from baseline in BASFI; ASAS partial remission(PR); change (improvement) from Baseline in Ankylosing SpondylitisQuality of Life (ASQoL); change (improvement) from baseline in ASASHealth Index (HI); change (improvement) from baseline in Linear BathAnkylosing Spondylitis Metrology Index (BASMIlin) (Mobility); and/orchange (improvement) from baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES) (Enthesitis). In certain embodiments, for anyof the aforementioned results achieved, a statistically significantpopulation of the subjects in the treated population, and/or at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 44%, or at least 45% of the subjects in thetreated population, achieve the result. In certain embodiments, for anyof the aforementioned results achieved, the subject (or subjects in thetreated population) achieve the result or results within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result (or results) is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of a method of reducing the signs and symptoms of AS,including active AS, wherein the subject achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), at least one result selected from the group consisting of: anASAS40 response; change (improvement) from baseline in ASDAS (e.g.,ASDAS CRP); change (improvement) from baseline in MRI SPARCC score forspine (MRI-Spine SPARCC); BASDAI50 response; ASAS20 response; ASDASinactive disease (ID); change (improvement) from baseline in Patient'sAssessment of Total Back Pain (Total Back Pain score); change(improvement) from baseline in Patient's Assessment of Nocturnal BackPain (Nocturnal Back Pain score); ASDAS low disease activity (LDA);(change (improvement) from baseline in BASFI; ASAS partial remission(PR); change (improvement) from Baseline in Ankylosing SpondylitisQuality of Life (ASQoL); change (improvement) from baseline in ASASHealth Index (HI); change (improvement) from baseline in Linear BathAnkylosing Spondylitis Metrology Index (BASMIlin) (Mobility); and/orchange (improvement) from baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES) (Enthesitis). In certain embodiments, for anyof the aforementioned results achieved, a statistically significantpopulation of the subjects in the treated population, and/or at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 44%, or at least 45% of the subjects in thetreated population, achieve the result. In certain embodiments, for anyof the aforementioned results achieved, the subject (or subjects in thetreated population) achieve the result or results within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result (or results) is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.

Further provided are methods of reducing the signs and symptoms of AS.In one aspect, provided is a method of reducing back pain, inflammation,physical function, mobility, and/or quality of life, the methodcomprising administering a dose of the JAK1 inhibitor to a subject inneed thereof in certain amounts and/or at certain intervals. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 14 weeks. In one aspect,the subject is bDMARD naïve. In one aspect, the subject is bDMARD-IR.

Further provided are methods of statistically significant treatment ofAS. In one aspect, provided is a method of statistically significanttreatment of AS, including active AS, in a subject or a population ofsubjects, the method comprising administering a dose of the JAK1inhibitor to a subject in need thereof or to subjects in the populationin certain amounts and/or at certain intervals, wherein the treatmentresults in a statistically significant higher ASAS40 response rate ascompared to placebo control within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14). In anotheraspect, the statistically significant higher ASAS40 response rate has ap value of less than 0.05. In one aspect, the statistically significanthigher ASAS40 response rate has a p-value of less than 0.01. In oneaspect, the statistically significant higher ASAS40 response rate has ap-value of less than 0.001. In one aspect, the statistically significanthigher ASAS40 response rate has a p value of less than 0.0001. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered in an amount sufficient to deliver a 15 mg dose ofupadacitinib. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR. In one aspect, thesubject is an adult.

Further provided are methods of reducing the signs and symptoms of AS.In one aspect, provided is a method of reducing back pain, inflammation,physical function, mobility, and/or quality of life, the methodcomprising administering a dose of the JAK1 inhibitor to a subject inneed thereof in certain amounts and/or at certain intervals. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 14 weeks. In one aspect,the subject is bDMARD naïve. In one aspect, the subject is bDMARD-IR.

Further provided are methods of statistically significant treatment ofAS. In one aspect, provided is a method of statistically significanttreatment of AS, including active AS, in a subject or a population ofsubjects, the method comprising administering a dose of the JAK1inhibitor to a subject in need thereof or to subjects in the populationin certain amounts and/or at certain intervals, wherein the treatmentresults in a statistically significant higher ASAS40 response rate ascompared to placebo control within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14). In anotheraspect, the statistically significant higher ASAS40 response rate has ap value of less than 0.05. In one aspect, the statistically significanthigher ASAS40 response rate has a p-value of less than 0.01. In oneaspect, the statistically significant higher ASAS40 response rate has ap-value of less than 0.001. In one aspect, the statistically significanthigher ASAS40 response rate has a p value of less than 0.0001. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered in an amount sufficient to deliver a 15 mg dose ofupadacitinib. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR. In one aspect, thesubject is an adult.

In another aspect, the subject has (or subjects in the treatedpopulation have) active AS at baseline. In one aspect, the subject (orsubjects in the treated population) fulfills the 1984 modified New YorkCriteria for AS at baseline. In another aspect, the subject (or subjectsin the treated population) fulfills the 2009 ASAS classificationcriteria at baseline. In yet another aspect, the subject (or subjects inthe treated population) fulfills the 1984 modified New York Criteria forAS and the 2009 ASAS classification criteria at baseline. In oneembodiment, the subject (or subjects in the treated population) meets atleast one criteria selected from the group consisting of: (i) a BASDAIscore ≥4; (ii) an ASDAS of ≥2.1; and (iii) a Patient's Assessment ofTotal Back Pain (Total Back Pain score) of ≥4 (based on a 0-10 numericalrating scale) at baseline. In one embodiment, the subject (or subjectsin the treated population) has both a BASDAI score ≥4 and a Patient'sAssessment of Total Back Pain (Total Back Pain score) of ≥4 at baseline.In another embodiment, the subject (or subjects in the treatedpopulation) has both a BASDAI score ≥4 and an ASDAS of ≥2.1 at baseline.In certain embodiments, the subject (or subjects in the treatedpopulation) has (i) a BASDAI score ≥4; (ii) an ASDAS of ≥2.1; and (iii)a Patient's Assessment of Total Back Pain (Total Back Pain score) of ≥4(based on a 0-10 numerical rating scale) at baseline. In one aspect, thesubject (or subjects in the treated population) does not have totalspinal ankylosis at baseline. In one aspect, the subject (or subjects inthe treated population) is an adult subject. In another aspect, thesubject (or subjects in the treated population) is a juvenile subject.

In another aspect, the subject has (or subjects in the treatedpopulation have) active AS at baseline. In one aspect, the subject (orsubjects in the treated population) fulfills the 1984 modified New YorkCriteria for AS at baseline. In one embodiment, the subject (or subjectsin the treated population) meets the following criteria at screening andbaseline: (i) a BASDAI score ≥4 and (ii) a Patient's Assessment of TotalBack Pain (Total Back Pain score) of ≥4 (based on a 0-10 numericalrating scale) at baseline. In one embodiment, the subject (or subjectsin the treated population) has both a BASDAI score ≥4 and a Patient'sAssessment of Total Back Pain (Total Back Pain score) of ≥4 at baseline.In one aspect, the subject (or subjects in the treated population) doesnot have total spinal ankylosis at baseline. In one aspect, the subject(or subjects in the treated population) is an adult subject. In anotheraspect, the subject (or subjects in the treated population) is ajuvenile subject.

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline. Exemplary bDMARDs include, but are not limitedto, a biologic tumor necrosis factor inhibitor (e.g., adalimumab,etanercept) and interleukin IL)-17 inhibitors (e.g., secukinumab,ixekizumab).

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and further has had i) an inadequate responseor intolerance to at least two NSAIDs (e.g., over at least a four-weekperiod at the maximum recommended or tolerated doses); ii) intoleranceto NSAIDs; and/or iii) contraindication for NSAIDs, as determined by aphysician. Examples of NSAIDs include, but are not limited to,traditional NSAIDs (e.g., ibuprofen) and salicylates (e.g., aspirin).

In certain aspects, the subject (or subjects in the treated population)to be treated is bDMARD naïve at baseline, has had an inadequateresponse or intolerance to at least two NSAIDS (as described above), oran intolerance to or contraindication for NSAIDS, and is furtherreceiving at least one additional therapy. Additional therapies include,but are not limited to concomitant administration of non-biologicDMARDs, NSAIDs, corticosteroids, and combinations thereof. Suitableadditional therapies for use in combination with the methods describedherein include:

-   -   1) Concomitant administration of non-biologic DMARDs, including        methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ),        and/or hydroxychloroquine (HCQ). In one embodiment, the subject        is on a stable dose of MTX (≤25 mg/week), SSZ (≤3 g/day),        hydroxychloroquine (≤400 mg/day), and/or leflunomide (≤20        mg/day) for at least 28 days prior to baseline. In some        embodiments, a combination of up to two background non-biologic        DMARDs is allowed, except the combination of MTX and        leflunomide. In one embodiment, the subject has not received any        non-biologic DMARDs (other than MTX, LEF, SSZ, and/or HCQ),        thalidomide, or apremilast within 28 days or five half-lives        (whichever is longer) prior to baseline.    -   2) Concomitant administration of oral corticosteroids. In one        embodiment, the subject is on a stable dose of prednisone (≤10        mg/day), or oral corticosteroid equivalents, for at least 14        days prior to baseline.    -   3) Concomitant administration of NSAIDs, tramadol, a combination        of acetaminophen and codeine or hydrocodone, and/or non-opioid        analgesics. In one embodiment, the subject is on stable dose(s)        for at least 14-days prior baseline.

In another aspect, the subject (or subjects in the treated population)is bDMARD-IR at baseline. In one aspect, the subject has had aninadequate response or intolerance to a bDMARD at baseline. Subjects whoare bDMARD-IR include those subjects who have had prior exposure to onebDMARD (either 1 tumor necrosis factor (TNF) inhibitor (e.g.,adalimumab, etanercept) or 1 interleukin (IL)-17 inhibitor (e.g.,secukinumab, ixekizumab)), and have discontinued the bDMARD due toeither intolerance or lack of efficacy (e.g., as determined by aphysician). In one embodiment, the subject (or subjects in the treatedpopulation) has not had prior exposure to a second bDMARD, if the reasonfor discontinuation was not due to lack of efficacy. In one embodiment,the subject (or subjects in the treated population) has not discontinuedboth a TNF inhibitor and an IL-17 inhibitor due to lack of efficacy.

In certain embodiments, the subject (or subjects in the treatedpopulation) has discontinued the bDMARD prior to receiving the firstdose of the JAK1 inhibitor for:

-   -   ≥4 weeks for etanercept;    -   ≥8 weeks for adalimumab, infliximab, certolizumab, golimumab,        abatacept, tocilizumab, and ixekizumab;    -   ≥12 weeks for ustekinumab;    -   ≥16 weeks for secukinumab;    -   ≥1 year for rituximab or ≥6 months if B cells have returned to        pre-treatment level or normal reference range (central lab) if        pre-treatment levels are not available; or    -   ≥12 weeks or at least 5 times the mean terminal elimination        half-life, whichever is longer, for other bDMARDs.

In one aspect, the subject (or subjects in the treated population) isbDMARD-IR a baseline, and further has had i) an inadequate response orintolerance to at least two NSAIDs (e.g., over at least a four weekperiod at the maximum recommended or tolerated doses); ii) intoleranceto NSAIDs; and/or iii) contraindication for NSAIDs. In one aspect, thesubject (or population of subjects) is bDMARD-IR, and has had aninadequate response to at least two NSAIDS or intolerance to and/orcontraindication for NSAIDs. Examples of NSAIDs include, but are notlimited to, traditional NSAIDs (e.g., ibuprofen) and salicylates (e.g.,aspirin).

In certain aspects, the subject (or subjects in the treated population)to be treated is bDMARD-IR at baseline, has had an inadequate responseor intolerance to at least two NSAIDS (as described above), and/or anintolerance to NSAIDs and/or contraindication for NSAIDS, and is furtherreceiving at least one additional therapy. Additional therapies include,but are not limited to concomitant administration of non-biologicDMARDs, NSAIDs, corticosteroids, and combinations thereof. Suitableadditional therapies for use in combination with the methods describedherein include:

-   -   1) Concomitant administration of non-biologic DMARDs, including        methotrexate (MTX), leflunomide, sulfasalazine (SSZ),        hydroxychloroquine, chloroquine, and/or apremilast. In one        embodiment, the subject is on a stable dose of MTX (≤25        mg/week), SSZ (≤3 g/day), hydroxychloroquine (≤400 mg/day),        chloroquine (≤400 mg/day); leflunomide (≤20 mg/day), or        apremilast (≤60 mg/day)), for at least 28 days prior to        baseline. In some embodiments, a combination of up to two        background non-biologic DMARDs is allowed, except the        combination of MTX and leflunomide.    -   2) Concomitant administration of oral corticosteroids. In one        embodiment, the subject is on a stable dose of prednisone (≤10        mg/day), or oral corticosteroid equivalents, for at least 14        days prior to baseline.    -   3) Concomitant administration of NSAIDs, tramadol, a combination        of acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone, and/or non-opioid        analgesics. In one embodiment, the subject is on stable dose(s)        for at least 14 days prior to baseline.

In one embodiment, the subject (or subjects in the treated population)is bDMARD-IR at baseline, has not been exposed to any JAK inhibitor, andhas not had any of the following treatments/conditions within thespecified time frame prior to baseline:

-   -   1) Intra-articular joint injections, spinal/paraspinal        injection(s), or parenteral administration of corticosteroids        within 28 days prior to baseline (not including inhaled or        topical corticosteroids);    -   2) Any other non-biologic DMARDs (other than those mentioned        above for concomitant treatment), including thalidomide, within        28 days or 5 half-lives (whichever is longer) of the drug prior        to baseline;    -   3) Opioid analgesics (except for combination of        acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone) within 14 days prior        to the Baseline Visit:    -   4) No live vaccine within 28 days (or longer if required        locally) prior to the first dose of JAK1 inhibitor, or have        expected need of live vaccination during treatment with the JAK1        inhibitor, including at least 30 days (or longer if required        locally) after the last dose of the JAK1 inhibitor;    -   5) No systemic use of known strong cytochrome P450 3A (CYP3A)        inhibitors during administration of the JAK1 inhibitor, or        strong CYP3A inducers 30 days prior to administration of the        JAK1 inhibitor through the end of treatment;    -   6) Herbal therapies or other traditional medicines with unknown        effects on CYP3A during treatment;    -   7) Investigational drug of chemical or biologic nature within a        minimum of 30 days or 5 half-lives of the drug (whichever is        longer) prior to the first dose of the JAK1 inhibitor; or    -   8) History of an allergic reaction or significant sensitivity to        constituents of the JAK1 inhibitor (and its excipients) and/or        other products in the same class.

In one embodiment, the subject (or subjects in the treated population)is bDMARD naïve or bDMARD-IR, and has not been previously exposed to anyJAK inhibitor at baseline.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and achieves an ASAS40 response within 14 weeks ofadministration of the first dose (including at week 14). In anotherembodiment, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and achieves an ASAS40 response within 2 weeksof administration of the first dose (including at week 2). In oneembodiment, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and achieves an ASAS40 response within 2 weeksof administration of the first dose (including at week 2) and maintainsthe ASAS40 response until at least 14 weeks after administration of thefirst dose (i.e., including until at least week 14). In one aspect, thesubject (or subjects in the treated population) further achieves ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks ofadministration of the first dose (including at week 2). In certainembodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and achieves an ASAS40 response within 14 weeks ofadministration of the first dose (including at week 14). In anotherembodiment, the subject is bDMARD-IR at baseline, and achieves an ASAS40response within 4 weeks of administration of the first dose (includingat week 4). In one embodiment, the subject achieves an ASAS40 responsewithin 4 weeks of administration of the first dose (including at week 2)and maintains the ASAS40 response until at least 14 weeks afteradministration of the first dose (i.e., including until at least week14). In one aspect, the subject (or population of subjects) furtherachieves change (improvement) from baseline in ASDAS (e.g., ASDAS CRP;ASDAS ESR); change (improvement) from baseline in MRI SPARCC score forspine (MRI-Spine SPARCC); BASDAI50 response; ASAS20 response; ASDASinactive disease (ID); change (improvement) from baseline in Patient'sAssessment of Total Back Pain (Total Back Pain score); change(improvement) from baseline in Patient's Assessment of Nocturnal BackPain (Nocturnal Back Pain score); ASDAS low disease activity (LDA);(change (improvement) from baseline in BASFI; ASAS partial remission(PR); change (improvement) from Baseline in Ankylosing SpondylitisQuality of Life (ASQoL); change (improvement) from baseline in ASASHealth Index (HI); change (improvement) from baseline in Linear BathAnkylosing Spondylitis Metrology Index (BASMIlin) (Mobility); and/orchange (improvement) from baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES) (Enthesitis) within 4 weeks of administrationof the first dose (including at week 4). In certain embodiments, for anyof the aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 44%, or at least 45% of the subjects in the treatedpopulation, achieved the result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and achieves within 14 weeks of administration of the firstdose (including at week 14) an improvement of ≥40% and absoluteimprovement of ≥2 units (on a scale of 0 to 10) from baseline in each ofthe following 4 (ASAS40) domains:

a) Patient Global Assessment of disease activity (PtGA) as assessed on anumeric rating scale (NRS 0-10);

b) Patient's Assessment of Total Back Pain (Total Back Pain score) asassessed on a numeric rating scale (NRS 0-10);

c) Bath Ankylosing Spondylitis Functional Index (BASFI); and

d) inflammation, as represented by the mean of Questions 5 and 6 of theBath Ankylosing Spondylitis Disease Activity Index (BASDAI).

In one embodiment, the above described improvements are achieved within2 weeks of administration of the first dose (including at week 2). Inone embodiment, the improvements are achieved within 14 weeks ofadministration of the first dose (including at week 14). In certainembodiments, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population, achieve the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration of the first dose (including at week 14) at least oneresult selected from the group consisting of: a) a change (improvement)from baseline in ASDAS (CRP); b) a change (improvement) from baseline inMRI SPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI50 response; e) a change (improvement) from baseline inBASFI; f) change from baseline in ASQoL; g) a change (improvement) frombaseline in ASAS Health Index (HI); h) a change (improvement) frombaseline in MASES (i.e., for subjects with baseline enthesitis); i) achange (improvement) from baseline in BASMIlin (mobility); and j) achange (improvement) from baseline in WPAI-Axial SpA. In one embodiment,the subject achieves the result within 2 weeks of administration of thefirst dose (including at week 2). In one embodiment, the subjectachieves the result within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: a) a change (improvement)from baseline in ASDAS; b) a change (improvement) from baseline in MRISPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI50 response; and e) a change (improvement) from baselinein BASFI. In one embodiment, each of the results are achieved within 14weeks of administration of the first dose (including at week 14). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result. Incertain embodiments, for any of the aforementioned results achieved, theresult (or results) is maintained or improved after achieving the result(or results) by continuing to administer a daily dose of the JAK1inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration of the first dose (including at week 14) at least oneresult selected from the group consisting of: k) ASAS 20 response; andl) a change (improvement) from baseline in MRI SPARCC score forsacroiliac (SI) joints (MRI-SI joints SPARCC). In one embodiment, eachof the results are achieved within 14 weeks of administration of thefirst dose (including at week 14). In certain embodiments, for any ofthe aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, or at least 45% of the subjects in the treated population,achieve at least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: m) ASAS20 response; n) ASAS40response; o) ASAS PR; p) ASAS 5/6 response; q) ASDAS Inactive Disease(based on ASDAS (CRP) and ASDAS (ESR)); r) ASDAS Low Disease; s) ASDASMajor Improvement (based on ASDAS (CRP) and ASDAS (ESR)); t) ASDASClinically Important Improvement (based on ASDAS (CRP) and ASDAS(ESR);u) change (improvement) from baseline in ASAS HI; v) change(improvement) from baseline in ASDAS(CRP) and ASDAS (ESR); w) change(improvement) from baseline in ASQoL; x) change (improvement) frombaseline in BASDAI; y) change (improvement) from baseline in BASFI; z)change (improvement) from baseline in BASMIlin; aa) change (improvement)from baseline in C-reactive protein (CRP); bb) change (improvement) frombaseline in FACIT-F; cc) change (improvement) from baseline in ISI; dd)change (improvement) from baseline in MASES (in subjects with baselineMASES >0); ee) change (improvement) from baseline in mASSS (withconventional radiograph); ff) change (improvement) from baseline in MRISPARCC score of SI joints; gg) change (improvement) from baseline in MRISPARCC score of spine; hh) change (improvement) from baseline inPatient's Assessment of Total Back Pain score (Total Back Pain score);ii) change (improvement) from baseline in Patient's Assessment ofNocturnal Back Pain (Nocturnal Back Pain); jj) change (improvement) frombaseline in Patient's Global Assessment of Pain (Pt Pain); kk) change(improvement) from baseline in Physician's Global Assessment of DiseaseActivity (PGA-Disease Activity); ll) change (improvement) from baselinein inflammation, as represented by the change (improvement) frombaseline in the mean of Questions 5 and 6 of the BASDAI; mm) change(improvement) from baseline in the Patient's Assessment of Total BackPain, as represented by a change (improvement) from baseline in question2 of BASDAI; nn) change (improvement) from baseline in peripheralpain/swelling, as represented by a change (improvement) in baseline inquestion 3 of BASDAI; oo) change (improvement) from baseline in durationof morning stiffness, as represented by a change (improvement) inbaseline in question 6 of BASDAI; pp) change (improvement) from baselinein Patient's Global Assessment of Disease Activity (PtGA); qq) change(improvement) from baseline in TJC68 and SJC66; rr) change (improvement)from baseline in WPAI-Axial SpA; ss) resolution (improvement) ofdactylitis in subjects with baseline presence of dactylitis; and tt)change (improvement) from baseline in total dactylitis count in subjectswith baseline presence of dactylitis. In certain embodiments, for any ofthe aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, or at least 45% of the subjects in the treated population,achieve at least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: q) ASDAS Inactive Disease;r) ASDAS Low Disease; s) ASDAS Major Improvement; and t) ASDASClinically Important Improvement. In one embodiment, each of the resultsare achieved within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population and/or at least 10%, at least 15%,at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, orat least 45% of the subjects in the treated population, achieved atleast one result. In certain embodiments, for any of the aforementionedresults achieved, the result (or results) is maintained or improvedafter achieving the result (or results) by continuing to administer adaily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: ASDAS Inactive Disease, ASDASModerate Disease, ASDAS Low Disease Activity (LDA), ASDAS High Disease,ASDAS Very High Disease, ASDAS Major Improvement, and ASDAS ClinicallyImportant Improvement. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and achieves an ASAS40 response within 14 weeks ofadministration of the first dose (including at week 14). In anotherembodiment, the subject is bDMARD-IR at baseline, and achieves an ASAS40response within 2 weeks of administration of the first dose (includingat week 2). In one embodiment, the subject achieves an ASAS40 responsewithin 2 weeks of administration of the first dose (including at week 2)and maintains the ASAS40 response until at least 14 weeks afteradministration of the first dose (i.e., including until at least week14). In one aspect, the subject (or population of subjects) furtherachieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within2 weeks of administration of the first dose (including at week 2). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieved the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: a) change (improvement)from baseline in ASDAS; b) change (improvement) from baseline in MRISPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI 50 response; e) change (improvement) from baseline inBASFI; f) change (improvement) from baseline in ASQoL; g) change(improvement) from baseline in ASAS Health Index (HI); h) change(improvement) from baseline in MASES (enthesitis); and i) change(improvement) from baseline in BASMIlin (mobility). In one embodiment,the result is achieved within 14 weeks of administration of the firstdose (including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: j) ASAS 20 response; and k)change (improvement) from baseline in MRI SPARCC score for SI joints(MRI-SI joints SPARCC). In one embodiment, the result is achieved within14 weeks of administration of the first dose (including at week 14). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result. Incertain embodiments, for any of the aforementioned results achieved, theresult (or results) is maintained or improved after achieving the result(or results) by continuing to administer a daily dose of the JAK1inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: l) ASAS20 response; m) ASAS40response; n) ASAS PR; o) ASDAS Inactive Disease; p) ASDAS Low Disease;q) ASDAS Major Improvement; r) ASDAS Clinically Important Improvement;s) discontinuation of opioids among subjects with opioid use atbaseline; t) change (improvement) from baseline in ASAS HI; u) change(improvement) from baseline in ASDAS; v) change (improvement) frombaseline in ASQoL; w) change (improvement) from baseline in BASDAI andBASDAI Questions, including change (improvement) from baseline in meanof question 5 and 6 of the BASDAI; x) change (improvement) from baselinein BASFI; y) change (improvement) from baseline in BASMIlin; z) change(improvement) from baseline in high sensitivity C-reactive protein(hsCRP); aa) change (improvement) from baseline in FACIT-F; bb) change(improvement) from baseline in EuroQoL-5D-5L (EQ-5D-5L); cc) change(improvement) from baseline in MASES; dd) change (improvement) frombaseline in mSASSS (with conventional radiograph); ee) change(improvement) from baseline in MRI SPARCC score of SI joints; ff) change(improvement) from baseline in MRI SPARCC score of spine; gg) change(improvement) from baseline in Patient's Assessment of Total Back Painscore (Total Back Pain score); hh) change (improvement) from baseline inPatient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain); ii)change (improvement) from baseline in Patient's Global Assessment ofPain (Pt Pain); jj) change (improvement) from baseline in Physician'sGlobal Assessment of Disease Activity (PGA-Disease Activity); kk) change(improvement) from baseline in Patient's Global Assessment of DiseaseActivity (PtGA); 11) change (improvement) from baseline in SF-36; mm)change (improvement) from baseline in TJC68 and SJC66; nn) change(improvement) from baseline in WPAI-Axial SpA; oo) change (improvement)from baseline in Change of NSAID score; and pp) change (improvement)from baseline in Physical Activity Assessment. In one embodiment, theresult is achieved within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

VIII. Methods of Treating Axial Spondyloarthritis

Provided herein are methods of treating axial spondyloarthritis (axSpA).In a particular aspect, provided are methods of treating active axSpA,which encompasses treating subjects with active ankylosing spondylitis(AS) and active non-radiographic axial spondyloarthritis (nr-axSpA),comprising administering orally once a day a dose of the JAK1 inhibitor,upadacitinib freebase, or a pharmaceutically acceptable salt thereof, toa subject in need thereof in certain amounts and/or at certainintervals. In one aspect, the JAK1 inhibitor is upadacitinib freebase.In one aspect, the JAK1 inhibitor is administered orally once a day inan amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 52 weeks.

Disease activity/severity for axSpA may be measured using a variety ofindexes, including the Assessment of SpondyloArthritis InternationalSociety (ASAS) responses (e.g., ASAS20, ASAS40, ASAS partial remission(PR), ASAS5/6); the Ankylosing Spondylitis Disease Activity Score(ASDAS), ASDAS low disease activity (LDA), ASDAS inactive disease (ID),ASDAS major improvement (MI), ASDAS clinically important improvement(CII), the magnetic resonance imaging (MRI) Spondyloarthritis ResearchConsortium of Canada (SPARCC) score for spine (MRI-Spine SPARCC); theMRI SPARCC score for sacroiliac (SI) joints (MRI-SI joints SPARCC); theBath Ankylosing Spondylitis Disease Activity Index (BASDAI); a BASDAI 50(BASDAI50) response; the Bath Ankylosing Spondylitis Functional Index(BASFI); the Ankylosing Spondylitis Quality of Life Questionnaire(ASQoL); the ASAS Health Index (HI); the Maastricht AnkylosingSpondylitis Enthesitis Score (MASES) (enthesitis); the Linear BathAnkylosing Spondylitis Metrology Index (BASMIlin) (mobility); the WorkProductivity and Activity Impairment Questionnaire—AxialSpondyloarthritis (WPAI-Axial SpA); high-sensitivity C-reactive proteinlevels (hsCRP); the Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) Questionnaire; the Insomnia Severity Index(ISI); the Modified Stroke Ankylosing Spondylitis Spine Score (mSASSS);the Patient's Assessment of Total Back Pain (Total Back Pain score); thePatient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain); thePatient's Global Assessment of Pain (Pt Pain); the Physician's GlobalAssessment of Disease Activity (PGA-Disease Activity); Inflammation(mean of Questions 5 and 6 of the BASDAI); Patient's Assessment of TotalBack Pain (Question 2 of BASDAI); Peripheral pain/swelling (Question 3of BASDAI); duration of morning stiffness (Question 6 of BASDAI);Patient's Global Assessment of Disease Activity (PtGA); tender jointcount (TJC68) and swollen joint count (SJC66); resolution of dactylitis;total dactylitis count; EuroQoL-5D-5L (EQ-5D-5L) Questionnaire; 36-ItemShort Form Health Survey (SF-36); Physical Activity Assessment, andNSAID score. These indexes are described in detail in the ClinicalEndpoint Definitions and Examples.

In one aspect, provided is a method of treating axSpA, including activeaxSpA, comprising administering a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein the subject achieves an Assessment ofSpondyloArthritis International Society 40 (ASAS40) response followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the JAK1inhibitor is administered orally once a day for at least 52 weeks.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer the daily dose. In one aspect, thesubject achieves an ASAS40 response within 2 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 2). In oneaspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer the daily dose. In one aspect, the subjectachieves an ASAS40 response within 52 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 52). In one aspect,the subject achieves an ASAS40 response within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52), and the response is maintained or improved after week 52 bycontinuing to administer the daily dose. In one aspect, the subjectachieves an ASAS40 response within 2 weeks, within 4 weeks, within 8weeks, within 12 weeks, within 14 weeks, within 18 weeks, within 24weeks, within 32 weeks, within 40 weeks, and/or within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2, week 4, week 8, week 12, week 14, week 18, week 24, week 32,week 40, and/or week 52). In one embodiment, the subject achieves anASAS40 response within 2 weeks of administration of the first dose(including at week 2) and maintains the ASAS40 response until at least14 weeks after administration of the first dose (e.g., until at leastweek 14). In one aspect, the JAK1 inhibitor is upadacitinib freebase. Inone aspect, the JAK1 inhibitor is administered in an amount sufficientto deliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 2 weeks,for at least 4 weeks, for at least 8 weeks, for at least 12 weeks, forat least 14 weeks, for at least 18 weeks, for at least 24 weeks, for atleast 32 weeks, for at least 40 weeks, and/or for at least 52 weeks. Inone embodiment, the JAK1 inhibitor is administered orally once a day forat least 14 weeks. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 52 weeks.

In another aspect, provided is a method of treating axSpA, includingactive axSpA, comprising administering the JAK1 inhibitor to a subjectin need thereof in certain amounts and/or at certain intervals asdescribed herein, wherein the subject achieves an ASAS40 response at acertain interval as described herein, and additionally achieves at leastone of the results set forth hereinafter for treatment of ankylosingspondylitis (AS) and/or non-radiographic axial spondyloarthritis(nr-axSpA) following administration of the JAK1 inhibitor. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 14 weeks. In one aspect,the JAK1 inhibitor is administered orally once a day for at least 52weeks.

In another aspect, provided is a method of treating axSpA, includingactive axSpA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of subjects in the treated population achieve an ASAS40response following administration of the JAK1 inhibitor (e.g., astatistically significant population of the subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 44%, or at least45% of the subjects in the treated population achieve the response). Inone aspect, the subjects in the treated population achieve an ASAS40response within 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theresponse is maintained or improved after week 14 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, subjects in the treated population achieve an ASAS40 responsewithin 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 52 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 52), and theresponse is maintained or improved after week 52 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, the subjects in the treated population achieve an ASAS40response within 2 weeks of administration of the first dose of the JAK1inhibitor (including at week 2). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 2 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 2), and theresponse is maintained or improved after week 2 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, subjects in the treated population achieve at least one of theresults set forth hereinafter for treatment of ankylosing spondylitis(AS) and/or non-radiographic axial spondyloarthritis (nr-axSpA)following administration of the JAK1 inhibitor (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 44%, or at least 45% of the subjectsin the treated population achieve at least one of the results). In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, adose of the JAK1 inhibitor is administered to the population in anamount sufficient to deliver 15 mg of upadacitinib freebase equivalent.In one aspect, the JAK1 inhibitor is administered to the subjects orallyonce a day for at least 14 weeks. In one aspect, the JAK1 inhibitor isadministered to the subjects orally once a day for at least 52 weeks.

Further provided are methods of reducing the signs and symptoms ofaxSpA. In one aspect, provided is a method of reducing the signs andsymptoms of axSpA, including active axSpA, comprising administering adose of the JAK1 inhibitor to a subject in need thereof in certainamounts and/or at certain intervals. In one aspect, the JAK1 inhibitoris upadacitinib freebase or a pharmaceutically acceptable salt thereof.In one aspect, the JAK1 inhibitor is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered once a day for 14 weeks. Inone aspect, the JAK1 inhibitor is administered once a day for 52 weeks.

In one aspect, the signs and symptoms of axSpA, including active axSpA,are reduced following administration of the JAK1 inhibitor when thesubject achieves, within 14 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 14), at least one result selectedfrom the group consisting of: an ASAS40 response; a change (improvement)from baseline in ASDAS (e.g., ASDAS CRP); a change (improvement) frombaseline in MRI SPARCC score for spine (MRI-Spine SPARCC); ASAS partialremission (PR); a BASDAI50 response; a change (improvement) frombaseline in BASFI; a change (improvement) from baseline in ASQoL; achange (improvement) from baseline in ASAS Health Index (HI); a change(improvement) from baseline in MASES (enthesitis); a change(improvement) from baseline in BASMIlin (mobility); a change(improvement) from baseline in WPAI-Axial SpA; and a change(improvement) from baseline in MRI SPARCC score for SI joints (MRI-SIjoints SPARCC); or when the subject achieves, within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52), an ASAS40 response. In one aspect, the subject achieves theresponse within 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14), and the response is maintained orimproved after week 14 by continuing to administer a daily dose of theJAK1 inhibitor. In another aspect, the subject achieves the responsewithin 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52), and the response is maintained orimproved after week 52 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, the subject achieves the response within2 weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.

For any of the methods of treating axSpA and/or methods for reducing thesigns and symptoms of axSpA described herein, the subject and/orsubjects in the treated population i) may be biologic disease-modifyinganti-rheumatic drug (bDMARD) naïve or ii) may have had an inadequateresponse or intolerance to a bDMARD (bDMARD-IR) at baseline. In certainembodiments, the subject (or subjects in the treated population) mayhave had a prior inadequate response to, intolerance to, orcontraindication to NSAIDs at baseline.

IX. Methods of Treating Non-Radiographic Axial Spondyloarthritis(nr-axSpA)

Further provided are methods of treating non-radiographic axialspondyloarthritis (nr-axSpA). In one aspect, provided are methods oftreating active nr-axSpA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals. In one aspect, the JAK1 inhibitor is upadacitinibfreebase. In one aspect, the JAK1 inhibitor is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered orally once a day for atleast 14 weeks. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 52 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

Disease activity/severity for nr-axSpA may be measured using a varietyof indexes, including those set forth above for the treatment of axSpA.In one particular aspect, provided is a method of treating nr-axSpA,including active nr-axSpA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals as described herein, wherein the subject achieves anAssessment of SpondyloArthritis International Society 40 (ASAS40)response following administration of the JAK1 inhibitor. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 14 weeks. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 52 weeks.In one aspect, the subject is bDMARD naïve. In one aspect, the subjectis bDMARD-IR.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 52 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 52). In one aspect, the subject achieves an ASAS40 response within52 weeks of administration of the first dose of the JAK1 inhibitor(including at week 52), and the response is maintained or improved afterweek 52 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, the subject achieves an ASAS40 response within 2weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within18 weeks, within 24 weeks, within 32 weeks, within 40 weeks, within 52weeks, within 104 weeks, and/or within 152 of administration of thefirst dose of the JAK1 inhibitor (including at week 2, week 4, week 8,week 12, week 14, week 18, week 24, week 32, week 40, week 52, week 104,and/or week 152). In one embodiment, the subject achieves an ASAS 40response within 2 weeks of administration of the first dose (includingat week 2), and maintains the ASAS40 response until at least 14 weeksafter administration of the first dose (e.g., until at least week 14).In one embodiment, the subject achieves an ASAS 40 response within 2weeks of administration of the first dose (including at week 2), andmaintains the ASAS40 response until at least 52 weeks afteradministration of the first dose (e.g., until at least week 52). In oneembodiment, the subject achieves an ASAS 40 response within 2 weeks ofadministration of the first dose (including at week 2), and maintainsthe ASAS40 response until at least 104 weeks after administration of thefirst dose (e.g., until at least week 104). In one embodiment, thesubject achieves an ASAS 40 response within 2 weeks of administration ofthe first dose (including at week 2), and maintains the ASAS40 responseuntil at least 152 weeks after administration of the first dose (e.g.,until at least week 152). In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 2 weeks, for at least 4 weeks, for at least 8weeks, for at least 12 weeks, for at least 14 weeks, for at least 18weeks, for at least 24 weeks, for at least 32 weeks, for at least 40weeks, for at least 52 weeks, for at least 104 weeks, and/or for atleast 152 weeks. In one embodiment, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the JAK1inhibitor is administered orally once a day for at least 52 weeks.

In one aspect, provided is a method of treating nr-axSpA, includingactive nr-axSpA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of the subjects in the treated population (e.g., astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 44%, or at least45% of the subjects in the treated population) achieve an ASAS40response following administration of the JAK1 inhibitor. In one aspect,subjects in the treated population achieve an ASAS40 response within 14weeks of administration of the first dose of the JAK1 inhibitor(including at week 14). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theresult is maintained or improved after week 14 by continuing toadminister a daily dose of the JAK1 inhibitor. In one aspect, subjectsin the treated population achieve an ASAS40 response within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52). In one aspect subjects in the treated population achieve anASAS40 response within 52 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 52), and the result is maintainedor improved after week 52 by continuing to administer a daily dose ofthe JAK1 inhibitor. In one aspect, the JAK1 inhibitor is upadacitinibfreebase. In one aspect, a dose of the JAK1 inhibitor is administered tothe subjects in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredto the subjects orally once a day for at least 14 weeks. In one aspect,the JAK1 inhibitor is administered to the subjects orally once a day forat least 52 weeks. In one aspect, the subjects in the population arebDMARD naïve. In one aspect, the subjects in the population arebDMARD-IR.

In one aspect of a method of treating nr-axSpA, including activenr-axSpA, the subject (or subjects in the treated population)additionally achieves within 14 weeks of administration of the firstdose of the JAK1 inhibitor (including at week 14), at least one resultselected from the group consisting of: a change (improvement) frombaseline in ASDAS; a change (improvement) from baseline in MRI-SI JointSPARCC; BASDAI50 response; ASDAS inactive disease (ID); a change(improvement) from baseline in Total Back Pain; a change (improvement)from baseline in Nocturnal Back Pain; ASDAS low disease activity (LDA);ASAS partial remission (PR); a change (improvement) from baseline inBASFI; a change (improvement) from baseline in ASQoL; a change(improvement) from baseline in ASAS Health Index (HI); ASAS20 response;a change (improvement) from baseline in MASES (enthesitis); and a change(improvement) from baseline in BASMIlin (mobility).

Further provided are methods of reducing the signs and symptoms ofnr-axSpA. In one aspect, provided is a method of reducing the signs andsymptoms of active nr-axSpA, in particular methods comprisingadministering a dose of the JAK1 inhibitor to a subject in need thereofin certain amounts and/or at certain intervals as described herein. Inone aspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect,the JAK1 inhibitor is administered in an amount sufficient to deliver 15mg of upadacitinib freebase equivalent. In one aspect, the JAK1inhibitor is administered orally once a day for at least 14 weeks. Inone aspect, the JAK1 inhibitor is administered orally once a day for atleast 52 weeks. In one aspect, the subject is bDMARD naïve. In oneaspect, the subject is bDMARD-IR.

In one aspect of a method of reducing the signs and symptoms ofnr-axSpA, including active nr-axSpA, the subject (or subjects in thetreated population) achieves within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), at least oneresult selected from the group consisting of: an ASAS40 response; achange (improvement) from baseline in ASDAS; a change (improvement) frombaseline in MRI-Spine SPARCC; ASAS partial remission (PR); a BASDAI50response; a change (improvement) from baseline in BASFI; a change(improvement) from baseline in ASQoL; a change (improvement) frombaseline in ASAS Health Index (HI); a change (improvement) from baselinein MASES (enthesitis); and a change (improvement) from baseline inBASMIlin (mobility); or the subject achieves within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52) an ASAS40 response. In one aspect, the subject (or subjects inthe treated population) achieves the result within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result is maintained or improved after week 14 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, the subject (or subjects in the treated population) achieves theresult within 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52), and the result is maintained orimproved after week 52 by continuing to administer a daily dose of theJAK1 inhibitor. In certain embodiments, for any of the aforementionedresults achieved, a statistically significant population of subjects inthe treated population, and/or at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population, achieve at least one result.

In one aspect of a method of reducing the signs and symptoms ofnr-axSpA, including active nr-axSpA, the subject (or subjects in thetreated population) achieves within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), at least oneresult selected from the group consisting of: an ASAS40 response; achange (improvement) from baseline in ASDAS; a change (improvement) frombaseline in MRI-SI Joint SPARCC; BASDAI50 response; ASDAS inactivedisease (ID); a change (improvement) from baseline in Total Back Pain; achange (improvement) from baseline in Nocturnal Back Pain; ASDAS lowdisease activity (LDA); ASAS partial remission (PR); a change(improvement) from baseline in BASFI; a change (improvement) frombaseline in ASQoL; a change (improvement) from baseline in ASAS HealthIndex (HI); ASAS20 response; a change (improvement) from baseline inMASES (enthesitis); and a change (improvement) from baseline in BASMIlin(mobility); or the subject achieves within 52 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 52) an ASAS40response. In one aspect, the subject (or subjects in the treatedpopulation) achieves the result within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), and the resultis maintained or improved after week 14 by continuing to administer adaily dose of the JAK1 inhibitor. In one aspect, the subject (orsubjects in the treated population) achieves the result within 52 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 52), and the result is maintained or improved after week 52 bycontinuing to administer a daily dose of the JAK1 inhibitor. In certainembodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 44%, or at least45% of the subjects in the treated population, achieve at least oneresult.

Further provided are methods of improving back pain, inflammation,physical function, and/or quality of life associated with nr-axSpA. Inone aspect, provided is a method of improving back pain, inflammation,physical function, and/or quality of life associated with activenr-axSpA, in particular methods comprising administering a dose of theJAK1 inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals as described herein. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the JAK1inhibitor is administered orally once a day for at least 52 weeks. Inone aspect, the subject is bDMARD naïve. In one aspect, the subject isbDMARD-IR.

Further provided are methods of statistically significant treatment ofnr-axSpA. In one aspect, provided is a method of statisticallysignificant treatment of nr-axSpA, including active nr-axSpA, in asubject or a population of subjects, the method comprising administeringa dose of the JAK1 inhibitor to a subject in need thereof or to subjectsin the population in certain amounts and/or at certain intervals,wherein the treatment results in a statistically significant higherASAS40 response rate as compared to placebo control within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14). In another aspect, the statistically significant higher ASAS40response rate has a p value of less than 0.05. In one aspect, thestatistically significant higher ASAS40 response rate has a p-value ofless than 0.01. In one aspect, the statistically significant higherASAS40 response rate has a p-value of less than 0.001. In one aspect,the statistically significant higher ASAS40 response rate has a p valueof less than 0.0001. In one aspect, the JAK1 inhibitor is upadacitinibfreebase. In one aspect, the JAK1 inhibitor is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered in an amount sufficient todeliver a 15 mg dose of upadacitinib. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 14 weeks. In one aspect,the subject is bDMARD naïve. In one aspect, the subject is bDMARD-IR. Inone aspect, the subject is an adult.

In one aspect, the subject (or population of subjects) in need oftreatment has active nr-axSpA at baseline. In one aspect, the subject(or subjects in the treated population) fulfills the 2009 ASASclassification criteria for axSpA, but does not meet the radiologiccriteria of the 1984 modified New York Criteria for AS at baseline. Inone embodiment, the subject (or subjects in the treated population)meets at least one criteria at baseline selected from the groupconsisting of: (i) a BASDAI score ≥4; (ii) an ASDAS of ≥2.1; (iii) aPatient's Assessment of Total Back Pain (Total Back Pain score) of ≥4(based on a 0-10 numerical rating scale); and (iv) an objective sign ofinflammatory activity selected from the group consisting of: a) anobjective sign of active inflammation on MRI of sacroiliac (SI) joints;and b) high-sensitivity C reactive protein (hsCRP)>upper limit of normal(ULN). In one aspect, the subject meets criteria (i), (ii), (iii), and(iv). In one aspect, the subject (or subjects in the treated population)is an adult subject. In another aspect, the subject (or subjects in thetreated population) is a juvenile subject.

In one aspect, the subject (or population of subjects) in need oftreatment has active nr-axSpA at baseline. In one aspect, the subject(or subjects in the treated population) fulfills the 2009 ASASclassification criteria for axSpA, but does not meet the radiologiccriteria of the 1984 modified New York Criteria for AS at baseline. Inone embodiment, the subject (or subjects in the treated population)meets the following criteria at screening and baseline: (i) a BASDAIscore ≥4; (ii) a Patient's Assessment of Total Back Pain (Total BackPain score) of ≥4 (based on a 0-10 numerical rating scale); and (iii) anobjective sign of inflammatory activity selected from the groupconsisting of: a) an objective sign of active inflammation on MRI ofsacroiliac (SI) joints; and b) high-sensitivity C reactive protein(hsCRP)>upper limit of normal (ULN). In one aspect, the subject meetscriteria (i), (ii), and (iii). In one aspect, the subject (or subjectsin the treated population) is an adult subject. In another aspect, thesubject (or subjects in the treated population) is a juvenile subject.

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline. Exemplary bDMARDs include, but are not limitedto, a biologic tumor necrosis factor inhibitor (e.g., adalimumab,etanercept) and interleukin (IL)-17 inhibitors (e.g., secukinumab,ixekizumab).

In another aspect, the subject (or subjects in the treated population)is bDMARD-IR at baseline. In one aspect, the subject (or subjects in thetreated population) has had an inadequate response or intolerance to abDMARD. Subjects who are bDMARD-IR include those subjects who have hadprior exposure to one bDMARD (either 1 tumor necrosis factor (TNF)inhibitor (e.g., adalimumab, etanercept) or 1 interleukin (IL)-17inhibitor (e.g., secukinumab, ixekizumab)), and have discontinued thebDMARD due to either intolerance or lack of efficacy (e.g., asdetermined by a physician). In one embodiment, the subject (or subjectsin the treated population) has not had prior exposure to a secondbDMARD, if the reason for discontinuation was not due to lack ofefficacy. In one embodiment, the subject (or subjects in the treatedpopulation) has not discontinued both a TNF inhibitor and an IL-17inhibitor due to lack of efficacy. In certain embodiments, the subject(or subjects in the treated population) has discontinued the bDMARDprior to receiving the first dose of the JAK1 inhibitor for:

-   -   ≥4 weeks for etanercept;    -   ≥8 weeks for adalimumab, infliximab, certolizumab, golimumab,        abatacept, tocilizumab, and ixekizumab;    -   ≥12 weeks for ustekinumab;    -   ≥16 weeks for secukinumab;    -   ≥1 year for rituximab or ≥6 months if B cells have returned to        pre-treatment level or normal reference range (central lab) if        pre-treatment levels are not available; or    -   ≥12 weeks or at least 5 times the mean terminal elimination        half-life, whichever is longer, for other bDMARDs.

In one aspect, the subject (or subjects in the treated population)further has had i) an inadequate response or intolerance to at least twoNSAIDs (e.g., over at least a four week period at the maximumrecommended or tolerated doses); ii) intolerance to NSAIDs; and/or iii)contraindication for NSAIDs at baseline. Examples of NSAIDs include, butare not limited to, traditional NSAIDs (e.g., ibuprofen) and salicylates(e.g., aspirin).

In certain aspects, the subject (or population of subjects) to betreated is further receiving at least one additional therapy. Additionaltherapies include, but are not limited to concomitant administration ofnon-biologic DMARDs, NSAIDs, corticosteroids, and combinations thereof.Suitable additional therapies for use in combination with the methodsdescribed herein include:

1) Concomitant administration of non-biologic DMARDs, includingmethotrexate (MTX), leflunomide, sulfasalazine (SSZ),hydroxychloroquine, chloroquine, or apremilast. In one embodiment, thesubject is on a stable dose of MTX (≤25 mg/week), SSZ (≤3 g/day),hydroxychloroquine (≤400 mg/day), chloroquine (≤400 mg/day); leflunomide(≤20 mg/day), or apremilast (≤60 mg/day)), for at least 28 days prior tobaseline. In some embodiments, a combination of up to two backgroundnon-biologic DMARDs is allowed, except the combination of MTX andleflunomide.

2) Concomitant administration of oral corticosteroids. In oneembodiment, the subject is on a stable dose of prednisone (≤10 mg/day),or oral corticosteroid equivalents, for at least 14 days prior tobaseline.

3) Concomitant administration of NSAIDs, tramadol, a combination ofacetaminophen/paracetamol and codeine or combination ofacetaminophen/paracetamol and hydrocodone, and/or non-opioid analgesics.In one embodiment, the subject is on stable dose(s) for at least 14 daysprior to baseline.

In one embodiment, the subject (or subjects in the treated population)has not been previously exposed to any JAK inhibitor at baseline.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves within 14 weeks of administration of the firstdose (including at week 14) at least one result selected from the groupconsisting of: a) a change (improvement) from baseline in ASDAS; b) achange (improvement) from baseline in MRI SPARCC score for SI joints(MRI-SI joints SPARCC); c) ASAS partial remission (PR); d) BASDAI50response; e) a change (improvement) from baseline in BASFI; f) change(improvement) from baseline in ASQoL; g) a change (improvement) frombaseline in ASAS Health Index (HI); h) a change (improvement) frombaseline in MASES (enthesitis); and i) a change (improvement) frombaseline in BASMIlin (mobility); In one embodiment, the subject achievesthe result within 2 weeks of administration of the first dose (includingat week 2). In one embodiment, the subject achieves each of the resultswithin 14 weeks of administration of the first dose (including at week14). In certain embodiments, for any of the aforementioned resultsachieved, the result (or results) is maintained or improved after week 2or week 14 by continuing to administer a daily dose of the JAK1inhibitor. In certain embodiments, for any of the aforementioned resultsachieved, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 44%, or atleast 45% of the subjects in the treated population, achieve at leastone result.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves within 14 weeks of administration of the firstdose (including at week 14) at least one result selected from the groupconsisting of: j) ASAS 20 response; and k) a change (improvement) frombaseline in MRI SPARCC score for spine (MRI-Spine SPARCC). In oneembodiment, each of the results is achieved within 14 weeks ofadministration of the first dose (including at week 14). In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after week 14 by continuing toadminister a daily dose of the JAK1 inhibitor. In certain embodiments,for any of the aforementioned results achieved, a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation, achieve at least one result.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves at least one result selected from the groupconsisting of: l) ASAS20 response; m) ASAS40 response; n) ASAS PR; o)ASDAS Inactive Disease; p) ASDAS Low Disease; q) ASDAS MajorImprovement; r) ASDAS Clinically Important Improvement; s)discontinuation of opioids among subjects with opioid use at baseline;t) change (improvement) from baseline in ASAS HI; u) change(improvement) from baseline in ASDAS; v) change (improvement) frombaseline in ASQoL; w) change (improvement) from baseline in BASDAI andBASDAI Questions, including change (improvement) from baseline in meanof questions 5 and 6 of the BASDAI; x) change (improvement) frombaseline in BASFI; y) change (improvement) from baseline in BASMIlin; z)change (improvement) from baseline in high sensitivity C-reactiveprotein (hsCRP); aa) change (improvement) from baseline in FACIT-F; bb)change (improvement) from baseline in EQ-5D-5L; cc) change (improvement)from baseline in MASES; dd) change (improvement) from baseline in mASSS(with conventional radiograph); ee) change (improvement) from baselinein MRI SPARCC score of SI joints; ff) change (improvement) from baselinein MRI SPARCC score of spine; gg) change (improvement) from baseline inPatient's Assessment of Total Back Pain score (Total Back Pain score);hh) change (improvement) from baseline in Patient's Assessment ofNocturnal Back Pain (Nocturnal Back Pain); ii) change (improvement) frombaseline in Patient's Global Assessment of Pain (Pt Pain); jj) change(improvement) from baseline in Physician's Global Assessment of DiseaseActivity (PGA-Disease Activity); kk) change (improvement) from baselinein Patient's Global Assessment of Disease Activity (PtGA); ll) change(improvement) from baseline in SF-36; mm) change (improvement) frombaseline in TJC68 and SJC66; nn) change (improvement) from baseline in(WPAI-Axial SpA); and oo) change (improvement) from baseline in Changeof NSAID score. In certain embodiments, for any of the aforementionedresults achieved, the result (or results) is maintained or improvedafter the result (or results) is achieved by continuing to administer adaily dose of the JAK1 inhibitor. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result.

EXAMPLES Examples 1-4: Extended Release Tablets

The Freebase Hydrate Form C and Amorphous Freebase solid state forms ofCompound 1 were formulated into 24 mg extended release tablets accordingto the formulations set forth in Table 4.

TABLE 4 Extended Release Tablets (no pH modifier) Ex. 1 Ex. 2 Ex .3(ER1) (ER2) (ER3) Ex. 4 Component Function (mg) (mg) (mg) (mg) FreebaseHydrate Form C Active 24.0 24.0 24.0 — Amorphous Freebase Active — — —24.0 Microcrystalline cellulose Filler 351.4 303.4 303.4 303.4 (Avicel ®PH 102) HPMC (Methocel ® K100 Release 96.0 96.0 — — Premium LVCRLH)control polymer HPMC (Methocel ® K4M Release — 48.0 144.0 144.0 PremiumCR) control polymer Colloidal silicon dioxide Glidant 3.8 3.8 3.8 3.8Magnesium stearate Lubricant 4.8 4.8 4.8 4.8 impalpable powder Uncoatedweight of tablet 480.0 480.0 480.0 480.0

The formulations were prepared by combining and blending the active,microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), andcolloidal silicone dioxide. The blend was milled using a Mobil Millfitted with a 610-micron screen. The magnesium stearate was screenedthrough mesh #30 and was added to the bin and blended.

The lubricated granulation was compressed into 480 mg weight tabletsusing a rotary tablet press. The tablets may optionally be coated withany suitable film coating.

The effect of solid state form on the dissolution profile of the tabletswas evaluated. In particular, the dissolution profile of the Example 3(containing Freebase Hydrate Form C as active) and Example 4 (containingAmorphous Freebase as active) tablets was evaluated at pH 6.8(representative of the pH in the lower intestine). The dissolution testwas carried out using the following dissolution parameters andconditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 900 mL of 50 mM sodium phosphate buffer solution, pH        6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

The medium used for the study was a 0.05 M sodium phosphate buffersolution, pH 6.8±0.05. The medium was prepared using an acid stagemedium (0.1 N hydrochloric acid solution) and a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The medium was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage concentratein an appropriate size container or directly in the dissolution vesseland adjusting the pH with 1 N phosphoric acid or 1 N sodium hydroxide,if the pH was not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 900 mL of the 0.05 M sodium phosphate buffer solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM, with 1.5 mL samples from the dissolution vesselautomatically obtained at the designated time periods. The samplefiltrate was the sample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % of the labelled amount of activereleased (% LA Released) was calculated. The formulation containingFreebase Hydrate Form C (Example 3) as the active showed a slower rateof dissolution than the formulation containing Amorphous Freebase(Example 4) as the active at pH 6.8.

The dissolution profile of formulations comprising Freebase Hydrate FormC as an active was further evaluated at pH 6.8 and in a dual pH system.In particular, the dissolution profile of the Example 1 (ER1), Example 2(ER2), and Example 3 (ER3) tablets at pH 6.8 was carried out asdescribed above. The dissolution profile of the Examples 1-3 tablets wasalso carried out in a dual pH system using the following dissolutionparameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: Acid Stage: 500 mL of Acid Stage Medium (0.1 N        hydrochloric acid solution)        -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer            solution, pH 6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour        -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid: 1.5 mL obtained automatically, without        media replacement.

The acid stage medium is a 0.1 N hydrochloric acid solution. A bufferstage medium for the study was prepared using a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The buffer stage medium of a 0.05 Msodium phosphate buffer solution, pH 6.8±0.05, was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage mediumconcentrate in an appropriate size container or directly in thedissolution vessel and adjusting the pH of the buffer stage mediumconcentrate with 1 N phosphoric acid or 1 N sodium hydroxide, if the pHwas not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of a 0.1 N hydrochloric acid solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM for 1 hour, and then a 1.5 mL sample from thedissolution vessel was automatically obtained. After the acid stagesample was obtained, 400 mL of buffer stage medium concentrate wasadded, maintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.

After the initial release at the low pH (representative of the pH in thestomach), release of the drug is slowed at the higher pH (representativeof the pH in the lower intestine). Therefore, in order to achieve thedesired bioavailability, a formulation which allowed pH independentrelease was required.

Examples 5-12: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 15 mg, 24 mg, or 30 mg extended release tabletsaccording to the formulations set forth in Table 5 using directcompression.

TABLE 5 Extended Release Tablets (tartaric acid pH modifier) Ex. 10 Ex.5 Ex. 8 Ex. 9 (mg) Ex. 11 Ex. 12 (mg) Ex. 6 Ex. 7 (mg) (mg) (ER4, no(mg) (mg) Component Function (ER7) (mg) (mg) (ER8) (ER4) mannitol) (ER5)(ER6) Freebase Active 15.4^(a) 15.4^(a) 15.4^(a) 30.7^(b) 24.6^(c)24.6^(c) 24.6^(c) 24.6^(c) Hydrate Form C Microcrystalline Filler 162.4162.4 162.4 147.1 158.0 210.6 282.6 258.6 cellulose (Avicel ® PH 102)Mannitol Filler 52.6 52.4 — 52.6 52.7 — — — (Pearlitol ® 100 SD)Mannitol Filler — — 52.4 — — — — — (Pearlitol ® 200 SD) Tartaric pH144.0 144.0 144.0 144.0 144.0 144.0 96.0 96.0 acid modifier HPMC Release96.0 — — 96.0 — — — (Hypromellose control 2208) polymer HPMC Release —96.0 96.0 — 96.0 96.0 — — (Methocel ® control K4M Premium polymer CR)Carbopol ® 71G Release — — — — — 48.0 72.1 control polymer Carbopol ®Release — — — — — 24.0 24.0 971P control polymer Colloidal Glidant 2.42.4 2.4 2.4 — — — — silicon dioxide Magnesium Lubricant 7.2 7.2 7.2 7.24.8 4.8 4.8 4.8 stearate impalpable powder Uncoated weight of tablet480.0 479.8 479.8 480.0 480.1 480.0 480.0 480.1 Opadry ® II Film coat14.40 — — 14.40 — — — — Yellow (PVA based) Total weight of tablet 494.39494.43 — — — — ^(a)Provides 15 mg of Compound 1 freebase equivalent.^(b)Provides 30 mg of Compound 1 freebase equivalent. ^(c)Provides 24 mgof Compound 1 freebase equivalent.

The formulations were prepared by first milling the tartaric acidthrough a Fitz mill Model M5A, fitted with a 1512-0027 screen. TheFreebase Hydrate Form C, microcrystalline cellulose, mannitol (whenpresent), milled tartaric acid, release control polymer, and colloidalsilicone dioxide (when present) were combined and blended. The blend wasmilled using a Mobil Mill fitted with a 610- or 1397-micron screen. Themagnesium stearate was screened through mesh #30 and was then added tothe bin and blended. The lubricated granulation was compressed intoabout 480 mg weight tablets using a rotary tablet press.

The Example 5 and 8 tablets were coated using a film coater, whichsprayed a solution containing the Opadry® II Yellow film coat andpurified water until 14.40 mg of coating had been applied to thetablets.

The dissolution profile of the Example 9 (ER4, 24 mg active), Example 10(ER4, no mannitol, 24 mg active), Example 11 (ER5, 24 mg active), andExample 12 (ER6, 24 mg active) tablets was evaluated at pH 1.2, at pH6.8, and in a dual pH system. The pH 6.8 study was performed asdescribed above for Examples 3 and 4. For the dual pH study, an acidstage medium of 0.05 M sodium phosphate solution, pH 3.5±0.05, wasprepared by dissolving about 41.4 g of sodium phosphate, monobasic,monohydrate in about 4 L of water, measuring the pH and addingphosphoric acid, 85%, dropwise as needed to adjust to the target pH. Themixture was diluted to 6 L with water and mixed. A buffer stage mediumfor the study was prepared using a buffer stage concentrate (0.05 Msodium phosphate buffer concentrate solution, prepared by dissolvingabout 41.4 g of sodium phosphate, monobasic, monohydrate and about 14.4g of sodium hydroxide pellets in about 4 L of water, dilute to 6 L withwater and mixing well). The buffer stage medium of a 0.05 M sodiumphosphate buffer solution, pH 6.8±0.05, was prepared by mixing 500 mL ofthe acid stage medium and 400 mL of buffer stage medium concentrate inan appropriate size container or directly in the dissolution vessel andadjusting the pH of the buffer stage medium concentrate with 1 Nphosphoric acid or 1 N sodium hydroxide, if the pH was not within6.8±0.05.

The dissolution test was carried out using the following dissolutionparameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: Acid Stage: 500 mL of Acid Stage Medium        -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer            solution, pH 6.8    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour        -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid and Buffer Stage: 1.5 mL obtained        automatically, without media replacement.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acid stage medium, maintained at 37° C.The paddles of the dissolution apparatus were operated at 75 RPM for 1hour, and then a 1.5 mL sample from the dissolution vessel wasautomatically obtained. After the acid stage sample was obtained, 400 mLof buffer stage medium concentrate was added, and then the mixture wasmaintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the pH 1.2 study, the dissolution test was carried out using thefollowing dissolution parameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 500 mL of Acidic Medium, pH 1.2    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

For this study, an acidic medium of 0.05 M sodium phosphate solution, pH3.5±0.05, was prepared by dissolving about 41.4 g of sodium phosphate,monobasic, monohydrate in about 4 L of water, measuring the pH andadding phosphoric acid, 85%, dropwise as needed to adjust to the targetpH of 1.2. The mixture was diluted to 6 L with water and mixed.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acidic medium, maintained at 37° C. Thepaddles of the dissolution apparatus were operated at 75 RPM, with 1.5mL samples from the dissolution vessel automatically obtained at thedesignated time periods. The sample filtrate was the sample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.The results shown that pH independence is achieved in the once dailyformulations.

The dissolution profile of the Example 5 (ER7), Example 8 (ER8), andExample 9 (ER4) tablets were evaluated in a dual pH system, as describedabove. The formulations provide an extended release profile of 80-100%over a period of about 8-10 hours.

The formulations of Examples 5 and 8-12 all exhibited pH independentrelease of the active ingredient. In contrast, after the initial releaseat the low pH, release of the active is slowed at the higher pH for theformulations of Examples 1-3. Without wishing to be bound to anyparticular theory, it is believed that the inclusion of tartaric acid asa pH modifier in the Example 5 and 8-12 formulations contributed to thepH independent release observed for these tablets.

Example 13: Extended Release Tablet

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into a 7.5 mg extended release tablet according to theformulation set forth in Table 6.

TABLE 6 Extended Release Tablets (tartaric acid pH modifier) Ex. 34 (mg)Component Function (ER9) Freebase Hydrate Form C* Active 7.678^(a)Microcrystalline Filler 170.1 cellulose (Avicel ® PH 102) Mannitol(Pearlitol ® 100 SD) Filler 52.62 Tartaric acid (crystalline) pHmodifier 144.0 HPMC (Hypromellose 2208) Release control 96.0 polymerColloidal silicon dioxide Glidant 2.4 Magnesium stearate Lubricant 7.2Uncoated weight of tablet 479.998 Opadry ® II Yellow Film coat 14.40Purified water Processing aid n/a Total weight of tablet 494.398^(a)Provides 7.5 mg of Compound 1 freebase equivalent.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model M5A, fitted with a 1512-0027 screen. The FreebaseHydrate Form C, microcrystalline cellulose, mannitol, milled tartaricacid, release control polymer, and colloidal silicone dioxide werecombined and blended. The blend was milled using a Mobil Mill fittedwith a 610-micron screen. The magnesium stearate was screened throughmesh #30 and was then added to the bin and blended. The lubricatedgranulation was compressed into about 480 mg weight tablets using arotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Examples 14-19: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 15 mg or 30 mg extended release tablets according to theformulations set forth in Table 7. The tablets were prepared using a wetgranulation process, and were compressed into tablets having a coreweight of about 480 mg.

TABLE 7 Extended Release Tablets (tartaric acid pH modifier) Ex. 14 Ex.15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 (mg) (mg) (mg) (mg) (mg) (mg) ComponentFunction (ER10) (ER11) (ER12) (ER13) (ER14) (ER15) Tablet Core(Intragranular) Freebase Hydrate Active 30.7^(a) 30.7^(a) 30.7^(a)15.4^(b) 15.4^(b) 15.4^(b) Form C Microcrystalline Filler 79.9 79.9 79.940.0 40.0 40.0 cellulose (Avicel ® PH 101) HPMC (Hypromellose Release9.5 9.5 9.5 4.8 4.8 4.8 2208) control polymer Tablet Core(Extragranular) Microcrystalline Filler 67.2 67.2 67.2 122.5 122.5 122.5cellulose (Avicel ® PH 102) Mannitol Filler 52.6 100.6 148.6 52.6 100.6148.6 Tartaric acid pH modifier 144.0 96.0 48.0 144.0 96.0 48.0(crystalline) HPMC (Hypromellose Release 86.5 86.5 86.5 91.2 91.2 91.22208) control polymer Colloidal silicon Glidant 2.4 2.4 2.4 2.4 2.4 2.4dioxide/silica Magnesium stearate Lubricant 7.2 7.2 7.2 7.2 7.2 7.2Uncoated weight of tablet 480.0 480.0 480.0 480.1 480.1 480.1 Opadry ®II Yellow^(c) Film coat 14.4 14.4 14.4 14.4 14.4 14.4 Total weight oftablet 494.4 494.4 494.4 494.5 494.5 494.5 ^(a)Provides 30 mg ofCompound 1 freebase equivalent. ^(b)Provides 15 mg of Compound 1freebase equivalent. ^(c)Film coat weight is approximate.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model M5A, fitted with a 1512-0027 screen. The intragranularportion of the hydroxypropylmethyl cellulose release control polymer,the Freebase Hydrate Form C, and intragranular portion of themicrocrystalline cellulose filler were added to a granulator, and mixed.Water was sprayed to granulate. The granulated material was then driedand milled using a comill fitted with a 610-micron screen. The milledgranulation was then added to the extragranular tablet components otherthan magnesium stearate, and sieved using a comill fitted with a1397-micron screen, followed by blending. The magnesium stearate wasthen added to the bin and blended. The lubricated granulation wascompressed into about 480 mg weight tablets using a rotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Example 20: Evaluation of the Effect of Organic Acids on DissolutionProfile of Extended Release Tablets

In this example, the effect of various organic acid pH modifiers (e.g.,tartaric acid, citric acid, succinic acid, and fumaric acid) on therelease rate of Freebase Hydrate Form C from 24 mg once-daily extendedrelease (ER) tablets was evaluated. Freebase Hydrate Form C wasformulated into 24 mg extended release tablets according to theformulations set forth in Table 8.

TABLE 8 Extended Release Tablets Tartaric acid Citric acid Succinic acidFumaric acid Component Function A B C D E F G H Freebase Hydrate Active24.6 24.6 24.6 24.6 24.6 24.6 24.6 24.6 Form C Microcrystalline Filler306.6 306.6 306.6 306.6 306.6 306.6 306.6 306.6 cellulose (Avicel ®PH102) HPMC (Methocel ® Release 96.0 — 96.0 — 96.0 — 96.0 — K4M) controlpolymer Carbopol ® 71G Release — 96.0 — 96.0 — 96.0 — 96.0 controlpolymer Organic acid pH 48.0 48.0 48.0 48.0 48.0 48.0 48.0 48.0 modifierMagnesium stearate Lubricant 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 Total 480.0480.0 480.0 480.0 480.0 480.0 480.0 480.0

The formulations were prepared by first milling the organic acid througha Fitz mill Model M5A, fitted with a 1512-0027 screen. The active,microcrystalline cellulose, milled organic acid, and release controlpolymer, were combined and blended. The blend was milled using a MobilMill fitted with a 610-micron screen. The magnesium stearate wasscreened through mesh #30 and was added to the bin and blended. Thelubricated granulation was compressed into 480 mg weight tablets using arotary tablet press.

The effect of the organic acids on the dissolution profile of thetablets was evaluated at pH 1.2 and pH 6.8. The dissolution tests werecarried out using the dissolution parameters and conditions as describedabove in Examples 3 and 4 and 9-12. For analysis of the sample,conventional liquid chromatography methods were utilized, wherein the %of the labelled amount of active released (% LA Released) wascalculated. The results show that organic acids improved dissolutionrate at high pH, with tartaric acid showing the best improvement. Theformulations comprising the control release polymer Carbopol® withtartaric acid provided near linear release at pH 6.8.

Example 21: Gel pH Measurements for Tablets with Different Amounts ofTartaric Acid

To measure the pH of the environment created when Compound 1 reacts withHPMC, the following experiment was performed.

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 30 mg extended release tablets according to theformulations set forth in Table 9A. The tablets were prepared using awet granulation process, as described in Examples 14-19.

Dissolution media of 0.01 N HCl (pH 2) and 113 mM sodium phosphatebuffer (pH 6.8) was prepared at 37° C. One tablet was added to 500 mL of0.01 N HCl media and stirred at 75 rpm at 37° C. for one hour in aVankel VK 7010 dissolution bath. Then 400 mL of sodium phosphate bufferwas added. The solution was stirred an additional three hours. Thetablet was removed, rinsed with water and dried using laboratorytissues. The gel that formed on the tablet was separated from the drycore for pH measurement. This procedure was repeated three times foreach formulation. The pH of the gel formed on the tablets is set forthin Table 9B.

TABLE 9A Formulations Formula- Formula- Formula- Formula- Formula- tion1 tion 2 tion 3 tion 4 tion 5 Component mg/tab mg/tab mg/tab mg/tabmg/tab Intragranular Freebase 30.71 30.71 30.71 30.71 30.71 Hydrate FormC HPMC 3.920 3.920 3.920 3.920 3.920 (Methocel ® K4M) Micro- 30.71 30.7130.71 30.71 30.71 crystalline cellulose (Avicel ® PH102) extragranularMicro- 116.4 164.4 188.4 212.4 260.4 crystalline cellulose (Avicel ®PH102) Tartaric Acid 144.0 96.00 72.00 48.00 0.00 (milled) Mannitol52.62 52.62 52.62 52.62 52.62 (Pearlitol ® 100SD) HPMC 92.08 92.08 92.0892.08 92.08 (Methocel ® K4M) Colloidal 2.400 2.400 2.400 2.400 2.400silicon dioxide Magnesium 7.200 7.200 7.200 7.200 7.200 Stearate Total480.04 480.04 480.04 480.04 480.04

TABLE 9B pH Results % Tartaric Formulation Acid 1^(st) tablet 2^(nd)tablet 3^(rd) tablet Average 1 30 2.63 2.68 2.81 2.71 2 20 3.17 3.093.23 3.16 3 15 3.42 3.94 3.65 3.67 4 10 3.88 3.67 3.77 3.77 5 0 6.266.21 6.55 6.34

Example 22: Evaluation of the In Vivo Pharmacokinetic Profile of 15 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 15 mg once-daily extended release(ER) tablets prepared in Example 5 was evaluated, and compared to thatof a 12 mg immediate-release (IR) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects (n=11) were administered a single dose of the 12mg IR capsule (Regimen A) and the 15 mg ER (once-daily) tablet fromExample 5 (Regimen B) under fasting conditions in a randomized,two-period, cross-over study design. Subjects were administered RegimenA in the first study period and Regimen B in the second study period, oradministered Regimen B in the first study period and Regimen A in thesecond study period. Serial blood samples were collected from eachsubject prior to dosing and for 72 hours after dosing in each studyperiod. Upon collection, the samples were promptly placed in an icebath, and within 2 hours after sample collection they were centrifugedat about 4° C. The resulting plasma samples were placed in cleanpolypropylene-tubes and stored in a freezer until analysis. The plasmasamples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter by regimen. The results are summarizedin Table 10A.

TABLE 10A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet and 12 mg IR CapsuleFormulations Under Fasting Conditions PK Regimen A Regimen B ParameterUnits (IR Capsule, 12 mg) (ER Tablet, 15 mg) C_(max) ng/mL 64.6 (16)26.0 (37) T_(max) ^(a) hours 1.0 (0.5-1.5) 3.0 (1.0-4.0) t_(1/2) ^(b)hours 9.2 (119) 12.5 (90) AUC_(t) ng · h/mL 231 (15) 227 (26) AUC_(inf)ng · h/mL 234 (15) 242 (26) ^(a)Median (minimum, maximum) ^(b)Harmonicmean (pseudo-% CV) ^(c)Data in parentheses is coefficient of variance ofthe PK parameter (% CV), unless otherwise indicated.

As can be seen from this data, the 15 mg ER tablet provided a lowerC_(max) and comparable AUC to the 12 mg IR capsule under fastingconditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen B) relative to the IR capsule formulation(Regimen A) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 10Bbelow.

TABLE 10B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment Relative Bioavailability PK 90% ConfidenceParameter Point Estimate Interval C_(max) 0.373 0.312-0.446 AUC_(t)0.939 0.869-1.013 AUC_(inf) 0.992 0.909-1.082

For Regimen B versus Regimen A, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.86-1.09 range.

Example 23: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 30 mg once daily extended release(ER) tablets prepared in Example 8 was evaluated, and compared to thatof a 24 mg dose of an immediate release (IR) capsule comprising TartrateHydrate as the active.

Healthy human subjects (n=12) were administered a single 24 mg dose (two12 mg IR capsules) (Regimen C) and the 30 mg ER (once daily) tablet fromExample 8 (Regimen D) under fasting conditions in a randomized,two-period, cross-over study design. Half the subjects were administeredRegimen C in the first study period and Regimen D in the second studyperiod, while the other half were administered Regimen D in the firststudy period and Regimen C in the second study period. Serial bloodsamples were collected from each subject prior to dosing and for 72hours after dosing in each study period. Upon collection, the sampleswere promptly placed in an ice bath, and within 2 hours after samplecollection they were centrifuged at about 4° C. The resulting plasmasamples were placed in clean polypropylene-tubes and stored in a freezeruntil analysis. The plasma samples were assayed for Compound 1 usingappropriate liquid chromatography mass spectrometry procedures.Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter byregimen. The results are summarized in Table 11A.

TABLE 11A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet and 24 mg Dose (2 × 12 mg)IR Capsule Formulations Under Fasting Conditions PK Regimen C Regimen DParameter Units (IR Capsules, 24 mg) (ER Tablet, 30 mg) C_(max) ng/mL176 (37) 63.7 (33) T_(max) ^(a) hours 0.5 (0.5-1.5) 2.0 (1.5-4.0)t_(1/2) ^(b) hours 9.9 (52) 10.8 (67) AUC_(t) ng · h/mL 520 (25) 477(27) AUC_(inf) ng · h/mL 524 (25) 491 (27) ^(a)Median (minimum-maximum)^(b)Harmonic mean (pseudo % CV) ^(c)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated.

As can be seen from this data, the 30 mg ER tablet provided a lowerC_(max) and comparable AUC to the 24 mg dose IR capsule (2×12 mg) underfasting conditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen D) relative to the IR capsule formulations(Regimen C) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 11Bbelow.

TABLE 11B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment PK Value Relative Bioavailability PK Regimen CPoint 90% Confidence Parameter Regimen D (reference) Estimate IntervalC_(max) 63.7 176 0.368 0.326-0.415 AUC_(t) 477 520 0.912 0.828-1.004AUC_(inf) 491 524 0.933 0.845-1.029

For Regimen D versus Regimen C, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.82-1.03 range.

Example 24: Comparison of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets Under Fasting Versus Fed Conditions

The pharmacokinetic profile of the 30 mg extended release tabletsprepared in Example 8 after a high-fat meal was evaluated, and comparedto the pharmacokinetic profile of the 30 mg extended release tabletsunder fasting conditions (see Example 23).

Following completion of the Example 23 study, the healthy human subjects(n=12) were administered single doses of the 30 mg ER (once daily)tablet from Example 8 after a high-fat meal (Regimen E). Serial bloodsamples were collected from each subject prior to dosing and for 72hours after dosing. Upon collection, the samples were promptly placed inan ice bath, and within 2 hours after sample collection they werecentrifuged at about 4° C. The resulting plasma samples were placed inclean polypropylene-tubes and stored in a freezer until analysis. Theplasma samples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter, and compared to the pharmacokineticparameters for the 30 mg tablets administered under fasting conditions(see Example 23, Regimen D). The results are summarized in Table 12A.

TABLE 12A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet Under Fasting Conditions orAfter a High-Fat Meal PK Regimen D Regimen E Parameter Units (Fasting)(After High-Fat Meal) C_(max) ng/mL 63.7 (33) 76.8 (39) T_(max) ^(a)hours 2.0 (1.5-4.0) 4.0 (1.5-8.0) t_(1/2) ^(b) hours 10.8 (67) 11.9 (51)AUC_(t) ng · h/mL 477 (27) 564 (26) AUC_(inf) ng · h/mL 491 (27) 577(27) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-CV %)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the once-daily (ER) 30mg tablet formulation after a high-fat meal (Regimen E) relative to thebioavailability of the ER 30 mg tablet under fasting conditions (RegimenD) was also determined based on analysis of the natural logarithms ofC_(max) and AUC. The results are summarized in Table 12B below.

TABLE 12B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment PK Value Regimen E Relative Bioavailability PK(after high- Regimen D Point 90% Confidence Parameter fat meal)(fasting) Estimate Interval C_(max) 76.8 63.7 1.197 1.027-1.395 AUC_(t)564 477 1.184 1.042-1.344 AUC_(inf) 577 491 1.171 1.035-1.326

As can be seen from Tables 13A and 13B, there is no clinicallymeaningful food effect for the 30 mg ER tablets. Administrationfollowing a high-fat meal increased the Compound 1 mean AUC and C_(max)by 17% and 20%, respectively.

Example 25: Observed Steady State Exposures for 15 mg and 30 mg ExtendedRelease Tablets Under Non-Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 5) and the 30 mg oncedaily ER tablets (prepared in Example 8) was evaluated.

Healthy human subjects (n=24) were assigned to one of two regimens.Subjects in Regimen F (n=12) were administered the 15 mg ER tablet fromExample 5 once daily for seven days under non-fasting conditions.Subjects in Regimen G (n=12) were administered the 30 mg ER tablet fromExample 8 once daily for seven days under non-fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Uponcollection, the samples were promptly placed in an ice bath, and within2 hours after sample collection they were centrifuged at about 4° C. Theresulting plasma samples were placed in clean polypropylene-tubes andstored in a freezer until analysis. The plasma samples were assayed forCompound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen. The results are summarized in Table 13A.

TABLE 13A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet or 30 mg ER Tablet QD forSeven Days (Non-Fasting) Regimen F Regimen G PK (15 mg ER Tablet) (30 mgER Tablet) Parameter Units Day 1 Day 7 Day 1 Day 7 C_(max) ng/mL 36.8(26) 36.0 (24) 74.3 (32) 79.5 (40) T_(max) ^(a) hours 4.0 (3.0-6.0) 4.0(2.0-6.0) 4.0 (2.0-6.0) 4.0 (1.5-6.0) AUC₂₄ ng · h/mL 305 (24) 317 (21)517 (30) 582 (30) C₂₄ ng/mL 2.42 (45) 3.22 (46) 4.27 (48) 5.25 (44)C_(trough) ng/mL — 2.96 (35) — 5.02 (42) C_(min, ss) ng/mL — 2.80 (41) —4.62 (38) Fluctuation Index % 291 (14) 251 (14) 345 (14) 306 (17)t_(1/2) ^(b) hours — 9.43 (76) — 10.4 (44) C_(max) to C₂₄ ratio 17(7.8-44) 13 (5.6-35) 17 (9.9-38) 14 (7.0-30) C_(max)/Dose (ng/mL)/mg2.46 (26) 2.40 (24) 2.48 (32) 2.65 (40) C_(trough)/Dose (ng/mL)/mg 0.16(45) 0.21 (46) 0.14 (48) 0.18 (44) AUC₂₄/Dose (ng · h/mL)/mg 20.3 (24)21.2 (21) 17.2 (30) 19.4 (30) R_(AUC) ^(c) — 1.02 (0.91-1.40) — 1.16(0.92-1.31) R_(Cmax) ^(d) — 1.00 (0.84-1.26) — 1.02 (0.82-1.40)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

As can be seen from this data, the observed steady state C_(max) andAUC₂₄ following 15 mg QD and 30 mg QD administration are generallyconsistent with the single dose and food-effect results obtained inprevious studies. The bioavailability of the 15 mg and 30 mg ER tabletsis 70% to 80% relative to the same dose of IR capsules.

Example 26: Observed Steady State Exposures for 15 mg Extended ReleaseTablets and 6 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 5) under fastingconditions was evaluated, and compared to that of a 6 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen K (n=12 at onset; n=11 on Day 7) were administeredthe 6 mg IR capsule twice daily for seven days under fasting conditions.Subjects in Regimen L (n=12) were administered the 15 mg ER tablet fromExample 5 once daily for seven days under fasting conditions. On daysone and seven, serial blood samples were collected from each subjectprior to the daily dosing and up to 24 hours after dosing. Blood sampleswere also collected at 48, 72, 96 and 120 hours after initial dosing.Upon collection, the samples were promptly placed in an ice bath, andwithin 2 hours after sample collection they were centrifuged at about 4°C. The resulting plasma samples were placed in clean polypropylene-tubesand stored in a freezer until analysis. The plasma samples were assayedfor Compound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen. The results are summarized in Table 14A.

TABLE 14A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 6 mg BID (IR) Capsules and 15 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen K Regimen L PK (6 mgIR Capsules (BID)) (15 mg ER Tablet (QD)) Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 36.5 (25) 33.9 (26) 31.7 (40) 31.9 (35)T_(max) ^(a) hours 1.0 (1.0-13) 1.0 (0.5-14) 3.0 (1.5-6.0) 2.5 (1.5-4.0)AUC₂₄ ng · h/mL 289 (21) 288 (22) 249 (29) 279 (26) C₁₂ ng/mL 2.0 (30)2.8 (24) — — C₂₄ ng/mL 3.2 (36) 3.6 (23) 1.9 (42) 3.1 (37) C_(min) ng/mL— 2.7 (26) — 3.1 (37) Fluctuation Index % 303 (13) 259 (13) 299 (22) 246(21) t_(1/2) ^(b) hours — 14.7 (77) — 10.3 (76) C_(max) to C₂₄ ratio^(a)— 12 (7.7-19) 8.8 (7.4-13) 22 (5.8-43) 12 (4.2-20) C_(max) to C_(min)ratio^(a) — — 13 (8.3-18) — 12 (4.2-20) AUC₂₄/Dose (ng · h/mL)/mg 24.8(23) 24.0 (22) 16.6 (29) 18.6 (26) R_(AUC) ^(c) — — 1.02 (0.88-1.09) —1.11 (0.87-1.99) R_(Cmax) ^(d) — — 0.97 (0.68-1.17) — 1.01 (0.65-3.01)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for the once-daily (ER) tablet formulation(Regimen L) relative to the twice daily (IR) capsule formulation(Regimen K) at steady state was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 14B below.

TABLE 14B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 15 mg QD Tablets Relative to 6 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability PK 90%Confidence Parameter Point Estimate Interval C_(max) 0.909 0.736-1.122AUC₂₄ 0.939 0.837-1.053 C_(min) 1.090 0.852-1.395

The ratio of steady-state AUC for the 15 mg QD tablets relative to the 6mg BID capsules was approximately 1, with the 90% confidence intervalswithin the equivalence boundaries. The ratio of the steady-state C_(min)was approximately 1 for the 15 mg QD tablet relative to the 6 mg BIDcapsules.

The pre-morning dose trough concentration (C_(trough)) for the 6 mg BIDcapsules and 15 mg QD tablets was determined prior to the morning doseon Days 2-8. At steady state under fasting conditions, the 15 mg QDtablets provided equivalent AUC₂₄ and comparable C_(max) and C_(min)relative to the 6 mg BID capsules. The steady state C_(max) was 10%lower for the 15 mg QD tablet compared to the 6 mg BID capsule.

Example 27: Observed Steady State Exposures for 30 mg Extended ReleaseTablets and 12 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 30 mg once dailyextended release (ER) tablets (prepared in Example 8) under fastingconditions was evaluated, and compared to that of a 12 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen M (n=11) were administered the 12 mg IR capsuletwice daily for seven days under fasting conditions. Subjects in RegimenN (n=12 at onset; n=11 at Day 7) were administered the 30 mg ER tabletfrom Example 8 once daily for seven days under fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Bloodsamples were also collected at 48, 72, 96 and 120 hours after initialdosing. Upon collection, the samples were promptly placed in an icebath, and within 2 hours after sample collection they were centrifugedat about 4° C. The resulting plasma samples were placed in cleanpolypropylene-tubes and stored in a freezer until analysis. The plasmasamples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter by regimen.

The results are summarized in Table 15A.

TABLE 15A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 12 mg BID (IR) Capsules and 30 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen M Regimen N PK (12mg IR Capsules (BID)) (30 mg ER Tablet (QD)) Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 80.8 (23) 73.9 (19) 65.7 (22) 68.2 (30)T_(max) ^(a) hours 1.0 (0.5-13) 1.0 (0.5-1.5) 2.5 (1.5-4.0) 3.0(2.0-4.0) AUC₂₄ ng · h/mL 497 (15) 534 (18) 454 (23) 525 (23) C₁₂ ng/mL3.0 (46) 4.1 (55) — — C₂₄ ng/mL 6.5 (54) 6.9 (37) 2.8 (37) 4.4 (39)C_(min) ng/mL — 3.8 (58) — 3.8 (43) Fluctuation Index % 388 (15) 317(14) 349 (12) 291 (17) t_(1/2) ^(b) hours — 7.3 (60) — 14.4 (64) C_(max)to C₂₄ ratio^(a) — 15 (5.4-20) 12 (5.9-16) 29 (13-38) 17 (4.1-33)C_(max) to C_(min) ratio^(a) — — 19 (8.4-31) — 17 (11-37) AUC₂₄/Dose (ng· h/mL)/mg 21.1 (15) 22.3 (18) 15.1 (22) 17.5 (23) R_(AUC) ^(c) — — 1.08(0.97-1.18) — 1.11 (0.79-1.67) R_(Cmax) ^(d) — — 0.98 (0.65-1.18) — 1.03(0.40-1.82) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)R_(AUC) = AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) =C_(max)Day 7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen N) relative to the twice daily (IR) capsuleformulation (Regimen M) was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 15B below.

TABLE 15B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 30 mg QD Tablets Relative to 12 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability PK 90%Confidence Parameter Point Estimate Interval C_(max) 0.900 0.732-1.107AUC₂₄ 0.974 0.869-1.092 C_(min) 0.874 0.747-1.022

The ratio of steady-state AUC for the 30 mg QD tablets relative to the12 mg BID capsules was approximately 1, with the 90% confidenceintervals within the equivalence boundaries. The steady-state C_(min)for the 30 mg QD tablet was approximately 13% lower than for the 12 mgBID capsules. Outliers with high C_(min) in the 12 mg BID dose may havecontributed to this difference.

The pre-morning dose trough concentration (C_(trough)) for the 12 mg BIDcapsules and 30 mg QD tablets was determined prior to the morning doseon Days 2-8. The results show that, at steady state under fastingconditions, the 30 mg QD tablets provided equivalent AUC₂₄ andcomparable C_(max) and C_(min) relative to the 12 mg BID capsules. Thesteady state C_(max) was 10% lower for the 30 mg QD tablet compared tothe 12 mg BID capsules.

Example 28: Comparison of AM vs. PM Pharmacokinetic Profile FollowingAdministration of 6 mg or 12 mg Immediate Release Capsules Under FastingConditions

The pharmacokinetic profile of the 6 mg immediate release (IR) twicedaily (BID) capsules and the 12 mg IR twice daily capsules wasdetermined on Day 7 of Regimen K (Example 26) and Regimen M (Example27), respectively, after administration of the morning (AM dose) andevening (PM dose). The results are summarized in Table 16.

TABLE 16 Mean (% CV)^(b) Pharmacokinetic Parameters for Compound 1Following Administration of AM and PM Doses of 6 mg and 12 mg ImmediateRelease Capsules on Day 7 (Fasting Conditions) Regimen K Regimen M PK (6mg IR Capsules) (12 mg IR Capsules) Parameter Units AM Dose PM Dose^(c)AM Dose PM Dose^(c) C_(max) ng/mL 33.6 (28) 24.4 (22) 73.9 (19) 46.0(26) T_(max) ^(a) hours 1 (0.5-1.5) 2 (1.0-3.0) 1 (0.5-1.5) 3 (1.0-4.0)AUC₁₂ ng · h/mL 152 (26) 153 (19) 290 (19) 244 (19) C₁₂ ng/mL 2.76 (24)3.63 (23) 4.1 (55) 6.94 (37) C_(max)/C₁₂ — 12.3 (23) 6.9 (22) 18.0 (30)7.4 (39) ^(a)Median (Minimum-Maximum) ^(b)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated ^(c)The PM dose was administered 3 hours after starting dinnerand 4 hours before a snack.

Example 29: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets

The pharmacokinetic profiles of the 30 mg once-daily extended release(ER) tablets that were prepared in Examples 14 (ER10, 30% tartaricacid), 15 (ER11, 20% tartaric acid), and 16 (ER12, 10% tartaric acid)using wet granulation were evaluated, and compared to that of the 30 mgER tablet that was prepared in Example 8 (ER8, 30% tartaric acid) usingdirect compression (no wet granulation). The effect of a high-fat mealon the Example 14, 15, and 16 formulations was also evaluated.

Healthy human subjects (n=36) were administered a single dose of the 30mg ER (once daily) tablet from Example 8 (ER8), Example 14 (ER10),Example 15 (ER11), and Example 16 (ER12) under fasting conditions orafter a high-fat meal (non-fasting), in an open-label, randomized,four-period, incomplete crossover study. Doses in the four periods wereseparated by at least four days. Dosing regimens were as set forth belowin Table 17A.

TABLE 17A Dosing Regimens Regimen Dose Formulation Fasting/Non-Fasting ASingle 30 mg Example 31 (ER8) Fasting B Single 30 mg Example 37 (ER10)Fasting C Single 30 mg Example 37 (ER10) Non-Fasting D Single 30 mgExample 38 (ER11) Fasting E Single 30 mg Example 38 (ER11) Non-Fasting FSingle 30 mg Example 39 (ER12) Fasting G Single 30 mg Example 39 (ER12)Non-Fasting

Serial blood samples were collected from each subject prior to dosingand for 72 hours after dosing in each study period. Upon collection, thesamples were promptly placed in an ice bath, and within 1 hour aftersample collection they were centrifuged at about 4° C. The resultingplasma samples were placed in clean polypropylene-tubes and stored in afreezer until analysis. The plasma samples were assayed for Compound 1using appropriate liquid chromatography mass spectrometry procedures.Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter byregimen.

Bioavailability Under Fasting Conditions

The results for administration under fasting conditions are summarizedin Table 17B.

TABLE 17B Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of a Single 30 mg Dose of Various Compound 1Once-Daily Formulations Prepared Using Wet Granulation Compared toAdministration of a Single 30 mg Dose of a Compound 1 Once-DailyFormulation Prepared Via Direct Compression Under Fasting Conditions PKRegimen A Regimen B Regimen D Regimen F Parameter Units (ER8) (n = 36)(ER10) (n = 24) (ER11) (n = 24) (ER12) (n = 24) C_(max) ng/mL 57.0 (33)55.8 (27) 61.0 (25) 58.6 (34) T_(max) ^(a) hours 2.5 (1.0-4.0) 3.0(1.0-4.0) 2.0 (1.0-4.0) 2.0 (1.0-4.0) AUC_(t) ng · h/mL 495 (24) 473(24) 487 (22) 481 (23) AUC_(inf) ng · h/mL 513 (26) 484 (24) 499 (22)495 (23) t_(1/2) ^(b) hours 9.2 (61) 10.1 (50) 9.0 (61) 9.3 (63)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)Data inparentheses is coefficient of variance of the PK parameter (% CV),unless otherwise indicated.

The relative bioavailability for a single dose of the three once-daily(ER) tablet formulations prepared using wet granulation (Regimens B, D,and F) relative to the ER tablet prepared via direct compression (no wetgranulation) (Regimen A) was also determined based on analysis of thenatural logarithms of C_(max), AUC_(t), and AUC_(inf). The results aresummarized in Table 17C below.

TABLE 17C Bioavailability for Three Compound 1 Once-Daily FormulationsPrepared Using Wet Granulation (30 mg; ER10, ER11, ER12) Relative to aFormulation Prepared Via Direct Compression (30 mg, ER8) under FastingConditions Relative Bioavailability PK Point 90% Confidence RegimensParamenter Estimate Interval Regimen B (ER10) C_(max) 1.024 0.917-1.143vs. AUC_(t) 0.990 0.933-1.049 Regimen A (ER8) AUC_(inf) 0.9760.918-1.037 Regimen D (ER11) C_(max) 1.063 0.952-1.187 vs. AUC_(t) 0.9850.929-1.044 Regimen A (ER8) AUC_(inf) 0.977 0.919-1.038 Regimen F (ER12)C_(max) 1.034 0.926-1.154 vs. AUC_(t) 0.958 0.904-1.016 Regimen A (ER8)AUC_(inf) 0.958 0.901-1.018

As can be seen from this data, all three of the 30 mg tablets preparedusing wet granulation (ER10, ER11, and ER12) were bioequivalent underfasting conditions to the tablet prepared via direct compression (no wetgranulation).

Effect of a High-Fat Meal on Example 37 Formulation (ER10)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 14 (ER10, 30 mg active, 30% tartaric acid) formulation issummarized in Table 17D.

TABLE 17D Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER10 under Fasting Conditions and After High-Fat MealRegimen B Regimen C PK (ER10, fasting) (ER10, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 55.8 (27) 76.3 (30) T_(max) ^(a)hours 3.0 (1.0-4.0) 4.0 (1.5-8.0) AUC_(t) ng · h/mL 473 (24) 605 (23)AUC_(inf) ng · h/mL 484 (24) 609 (23) t_(1/2) ^(b) hours 10.1 (50) 9.1(35) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 14formulation (ER10) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 17E below.

TABLE 17E Bioavailability of Single Dose of the 30 mg Once- Daily TabletER10 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate Interval Regimen C (ER10, high-fat C_(max) 1.322 1.134-1.541meal) AUC_(t) 1.296 1.194-1.405 vs. AUC_(inf) 1.278 1.174-1.392 RegimenB (ER10, fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER10 formulation (30 mg active, 30% tartaric acid) byabout 32% and 28%, respectively.

Effect of a High-Fat Meal on Example 38 Formulation (ER11)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 15 (ER11, 30 mg, 20% tartaric acid) formulation is summarized inTable 17F.

TABLE 17F Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER11 under Fasting Conditions and After High-Fat MealRegimen D Regimen E PK (ER11, fasting) (ER11, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 61.0 (25) 82.2 (33) T_(max) ^(a)hours 2.0 (1.0-4.0) 4.0 (3.0-8.0) AUC_(t) ng · h/mL 487 (22) 648 (24)AUC_(inf) ng · h/mL 499 (22) 657 (24) t_(1/2) ^(b) hours 9.0 (61) 9.7(53) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 15formulation (ER11) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 17G below.

TABLE 17G Bioavailability of Single Dose of the 30 mg Once- Daily TabletER11 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate Interval Regimen E (ER11, high-fat C_(max) 1.343 1.153-1.563meal) AUC_(t) 1.305 1.204-1.415 vs. AUC_(inf) 1.285 1.181-1.398 RegimenD (ER11, fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER11 formulation (30 mg active, 20% tartaric acid) byabout 34% and 29%, respectively, which was a similar food effect as thatobserved for the Example 14 (ER10) tablet.

Effect of a High-Fat Meal on Example 16 Formulation (ER12)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 16 (ER12, 30 mg active, 10% tartaric acid) formulation issummarized in Table 17H.

TABLE 17H Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER12 under Fasting Conditions and After High-Fat MealRegimen E Regimen G PK (ER12, fasting) (ER12, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 58.6 (34) 84.2 (33) T_(max) ^(a)hours 2.0 (1.0-4.0) 4.0 (4.0-6.0) AUC_(t) ng · h/mL 481 (23) 615 (24)AUC_(inf) ng · h/mL 495 (23) 622 (23) t_(1/2) ^(b) hours 9.3 (63) 11.7(91) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 16formulation (ER12) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max) AUC_(t), and AUC_(inf).The results are summarized in Table 171 below.

TABLE 17I Bioavailability of Single Dose of the 30 mg Once-Daily TabletER12 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate Interval Regimen G (ER12, high-fat C_(max) 1.527 1.314-1.774meal) AUC_(t) 1.295 1.196-1.402 vs. AUC_(inf) 1.272 1.171-1.381 RegimenF (ER12, fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER12 formulation (30 mg active, 10% tartaric acid) byabout 53% and 27%, respectively.

Example 30: Predicted Pharmacokinetic Parameters for 15 mg ExtendedRelease Tablets

The mean pharmacokinetic parameters under fasting conditions for theonce daily (QD) 15 mg extended release tablets prepared in Examples 17(ER13), 18 (ER14), and 19 (ER15) using wet granulation were extrapolatedfrom the single dose data obtained in Example 29 for the Examples 14(ER10), 15 (ER11), and 16 (ER12) formulations, respectively, underfasting conditions. The results are set forth in Table 18A.

TABLE 18A Predicted Mean Pharmacokinetic Parameters under FastingConditions for Compound 1 Following Administration of Single 15 mgOnce-Daily Formulations (Extrapolated from Single-Dose Profiles inExample 52 for 30 mg Doses) Single 15 mg Single 15 mg Single 15 mg PKParameters Units Dose (ER 13) dose (ER14) dose (ER15) C_(max) ng/mL 27.930.5 29.3 T_(max) ^(a) h 3.0 2.0 2.0 AUC_(inf) ng · h/mL 242 250 248^(a)Median (minimum-maximum)

Example 31: A Phase 2/3 Ankylosing Spondylitis Clinical Study(SELECT-AXIS 1)

SELECT-AXIS 1 is a multicentre, randomised, double-blind,parallel-group, placebo-controlled, Phase 2/3, two-period study ofupadacitinib (FIG. 1 ). 15 mg upadacitinib refers to the 15 mgonce-daily (QD) upadacitinib Extended Release (ER) Wet GranulatedTablets drug product as described herein are provided in the followingTable 19A. The 15 mg upadactinib ER tablet (or matching placebo) istaken orally once daily, beginning on Day 1 (Baseline), and should betaken at approximately the same time each day, with or without food.

TABLE 19A Upadacitinib 15 mg Extended Release (ER) Tablets (WetGranulated) Component Function Weight Tablet Core IntragranularUpadacitinib* Drug substance 15.4 Microcrystalline cellulose Filler 41.2(≥65% through 75 um screen) (Avicel PH 102) Hypromellose 2208 Controlrelease 4.9 polymer and binder Purified water Wetting agent N/AExtragranular Microcrystalline cellulose Filler 121.3 (≥65% through 75um screen) (Avicel PH 102) Mannitol (Pearlitol 100 SD) Filler 100.6Tartaric acid powder pH modifier 96.0 Hypromellose 2208 Control release91.1 polymer Colloidal Silicon Dioxide Glidant 2.4 Magnesium StearateLubricant 7.2 Film Coat OPADRY II Yellow (PVA, Film coat 14.40 TiO₂,PEG3350, Talc, Iron Oxide Yellow) Purified water** Processing Aid N/A*hemihydrate upadacitinib free base Form C as disclosed in WO2017066775and WO 2018/165581 is used. 15 mg amount per tablet refers to the amountof anhydrous upadacitinib free base in the tablet; **removed duringprocessing.

Period 1 is the 14-week randomized, double-blind, parallel-group,placebo-controlled period designed to compare the safety and efficacy ofupadacitinib free base 15 mg QD (once daily) versus placebo for thetreatment of signs and symptoms of subjects with active AS who have hadan inadequate response to at least two NSAIDs over an at least 4-weekperiod in total at maximum recommended or tolerated doses or intoleranceto or a contraindication for NSAIDs, and who are biologic DiseaseModifying Anti-Rheumatic Drug (bDMARD)-naïve.

Period 2 is an open label long-term extension to evaluate the long-termsafety, tolerability, and efficacy of upadacitinib free base 15 mg QD insubjects with AS who have completed Period 1.

X-rays of the pelvis were performed within the 35-day screening periodto evaluate the SI joints to confirm the fulfillment of the modified NewYork Criteria for AS. X-rays of the spine were also performed within the35-day screening period to assess for total spinal ankylosis; subjectswith total spinal ankylosis were not eligible for this study. The x-raysof the spine and pelvis were not required during the Screening Period ifthe subject had a previous anteroposterior (AP) pelvis x-ray and lateralspine x-rays within 90 days of the Screening Period, provided that thex-rays are confirmed to be adequate for the required evaluations and aredeemed acceptable by the central imaging vendor.

Subjects who met eligibility criteria were randomized in a 1:1 ratio toone of two treatment groups:

-   -   Group 1: Upadacitinib free base 15 mg QD, N=85 (Day 1 to Week        14)→Upadacitinib free base 15 mg QD (Week 14 and thereafter)    -   Group 2: Placebo, N=85 (Day 1 to Week 14)→Upadacitinib free base        15 mg QD (Week 14 and thereafter)

Starting at Week 16, subjects who did not achieve at least an ASAS 20response at two consecutive visits had the option to add or modify dosesof NSAIDs, acetaminophen/paracetamol, low potency opioid medications(tramadol or combination of acetaminophen and codeine or hydrocodone),and/or modify dose of MTX or SSZ at Week 20 or thereafter.

Starting at Week 24, subjects who still did not achieve at least an ASAS20 response at two consecutive visits were discontinued from study drugtreatment.

Subjects who completed the Week 14 visit (end of Period 1) entered theopen-label long-term extension portion of the study, Period 2 (90weeks). Subjects who were assigned to Upadacitinib in Period 1 continuedto receive Upadacitinib free base 15 mg QD in an open-label manner.Subjects who were randomized to placebo at Baseline also receivedopen-label upadacitinib free base 15 mg QD at Week 14.

Main Inclusion Criteria:

-   -   1 Male or female ≥18 years of age.    -   2 Subject with a clinical diagnosis of AS and meeting the        modified New York Criteria for AS.    -   3 Subject must have baseline disease activity as defined by        having a Bath Ankylosing Spondylitis Disease Activity Index        (BASDAI) score ≥4 and a Patient's Assessment of Total Back Pain        score (Total Back Pain score) ≥4 based on a 0-10 Numeric Rating        Scale (NRS) at the Screening and Baseline Visits.    -   4 Subject has had an inadequate response to at least two NSAIDs        over an at least 4-week period in total at maximum recommended        or tolerated doses, or subject has an intolerance to or        contraindication for NSAIDs.    -   5 If entering the study on concomitant methotrexate (MTX),        leflunomide, sulfasalazine (SSZ), and/or hydroxychloroquine,        subject must be on a stable dose of MTX (≤25 mg/week) and/or SSZ        (≤3 g/day) and/or hydroxychloroquine (≤400 mg/day) or        leflunomide (≤20 mg/day) for at least 28 days prior to the        Baseline Visit. A combination of up to two background        conventional-synthetic disease modifying anti-rheumatic drugs        (csDMARDs) is allowed EXCEPT the combination of MTX and        leflunomide.    -   6 If entering the study on concomitant oral corticosteroids,        subject must be on a stable dose of prednisone (≤10 mg/day), or        oral corticosteroid equivalents, for at least 14 days prior to        the Baseline Visit.    -   7 If entering the study on concomitant NSAIDs, tramadol,        combination of acetaminophen and codeine or hydrocodone, and/or        non-opioid analgesics, subject must be on stable dose(s) for at        least 14 days prior to the Baseline Visit.        Main Exclusion Criteria:    -   1 Patients with total spinal ankylosis were ineligible.    -   2 Prior exposure to any Janus kinase (JAK) inhibitor (including        but not limited to tofacitinib, baricitinib, and filgotinib).    -   3 Prior exposure to any biologic therapy with a potential        therapeutic impact on spondyloarthritis (SpA).    -   4 Intra-articular joint injections, spinal/paraspinal        injection(s), or parenteral administration of corticosteroids        within 28 days prior to the Baseline Visit. Inhaled or topical        corticosteroids are allowed.    -   5 Subject on any other DMARDs (other than those allowed),        thalidomide, or apremilast within 28 days or five half-lives        (whichever is longer) of the drug prior to the Baseline Visit.    -   6 Subject on opioid analgesics (except for combination        acetaminophen/codeine or acetaminophen/hydrocodone which are        allowed) or use of inhaled marijuana within 14 days prior to the        Baseline Visit.    -   7 Subject has a history of inflammatory arthritis of different        etiology other than axial SpA (including but not limited to        rheumatoid arthritis [RA], psoriatic arthritis [PsA], mixed        connective tissue disease, systemic lupus erythematosus,        reactive arthritis, scleroderma, polymyositis, dermatomyositis,        fibromyalgia), or any arthritis with onset prior to 17 years of        age.        Primary Endpoint

The primary efficacy endpoint is ASAS 40 response at Week 14.

Key Secondary Endpoints

The key multiplicity adjusted secondary efficacy endpoints at Week 14are:

-   -   1. Change from Baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS(CRP));    -   2. Change from Baseline in MRI Spondyloarthritis Research        Consortium of Canada (SPARCC) score (Spine);    -   3. Proportion of subjects with BASDAI 50 response (defined as        50% improvement in the Bath AS Disease Activity Index);    -   4. Change from Baseline in AS quality of life (ASQoL);    -   5. Proportion of subjects with ASAS partial remission (PR)        (defined as an absolute score of ≤2 units for each of the four        domains identified in ASAS 40);    -   6. Change from Baseline in BASFI;    -   7. Change from Baseline in BASMI_(lin);    -   8. Change from Baseline in Maastricht Ankylosing Spondylitis        Enthesitis Score (MASES) (i.e., for subjects with baseline        enthesitis);    -   9. Change from Baseline in Work Productivity and Activity        Impairment (WPAI) (the overall work impairment due to SpA);    -   10. Change from Baseline in ASAS HI.

Additional key secondary endpoints are:

-   -   11. ASAS 20 response at Week 14.    -   12. Change from Baseline in MRI SPARCC score (SI joints) at Week        14.

Additional endpoints are the following measurements assessed in subjectstreated with upadacitinib versus placebo at scheduled time points otherthan those specified for the primary and key secondary variables:

-   -   1. Proportion of subjects with ASAS 20 response;    -   2. Proportion of subjects with ASAS 40 response;    -   3. Proportion of subjects with ASAS PR;    -   4. Proportion of subjects with ASAS 5/6 (20% improvement from        Baseline in five out of the following six domains: BASFI,        patient's assessment of total back pain, PtGA, inflammation        [mean of Questions 5 and 6 of the BASDAI] lateral lumbar flexion        from BASMIlin, and high sensitivity CRP [hsCRP]);    -   5. Proportion of subjects with Inactive Disease based on        ASDAS(CRP) and ASDAS(ESR) (ASDAS score <1.3);    -   6. Proportion of subjects with Major Improvement based on        ASDAS(CRP) and ASDAS(ESR) (a change from Baseline <−2.0);    -   7. Proportion of subjects with Clinically Important Improvement        based on ASDAS(CRP) and ASDAS(ESR) (a change from Baseline        ≤−1.1);    -   8. Proportion of subjects with Resolution of dactylitis (i.e.,        for subjects with baseline presence of dactylitis);    -   9. Change from Baseline in ASAS HI;    -   10. Change from Baseline in ASDAS(CRP) and ASDAS(ESR)        respectively;    -   11. Change from Baseline in AsQoL;    -   12. Change from Baseline in BASDAI;    -   13. Change from Baseline in BASFI;    -   14. Change from Baseline in BASMIlin;    -   15. Change from Baseline in CRP;    -   16. Change from Baseline in Total dactylitis count (i.e., for        subjects with baseline presence of dactylitis);    -   17. Change from Baseline in FACIT-F;    -   18. Change from Baseline in ISI;    -   19. Change from Baseline in MASES (i.e., for subjects with        baseline MASES >0);    -   20. Change from Baseline in Modified Stoke Ankylosing        Spondylitis Spine Score (mSASSS) score with conventional        radiograph;    -   21. Change from Baseline in MRI SPARCC score of SI joints;    -   22. Change from Baseline in MRI SPARCC score of Spine;    -   23. Change from Baseline in Patient's Assessment of Total Back        Pain NRS score 0-10;    -   24. Change from Baseline in Patient's Assessment of Nocturnal        Back Pain NRS score 0-10;    -   25. Change from Baseline in Patient's Global Assessment of Pain        NRS score 0-10;    -   26. Change from Baseline in Physician's Global Assessment of        Disease Activity NRS score 0-10;    -   27. Change from Baseline in Inflammation (mean of Questions 5        and 6 of BASDAI NRS scores 0-10);    -   28. Change from Baseline in Patient's assessment of total back        pain (BASDAI Question 2 NRS score 0-10);    -   29. Change from Baseline in Peripheral pain/swelling (BASDAI        Question 3 NRS score 0-10);    -   30. Change from Baseline in Duration of morning stiffness        (BASDAI Question 6 NRS score 0-10);    -   31. Change from Baseline in Patient's Global Assessment of        Disease Activity NRS score 0-10;    -   32. Change from Baseline in TJC68 and SJC66;    -   33. Change from Baseline in WPAI (all 4 dimension scores);    -   34. Change from Baseline in Categories in ISI. See, e.g.,        Machado et al., Ann Rheum Dis (2018) 77: 1539-40; Maksymowych et        al., Arthritis Rheum (2005) 53: 502-9.        Analysis Windows

For each protocol-specified study visit, a target study day will beidentified to represent the corresponding visit along with a windowaround the target day. Windows will be selected in a non-overlappingfashion so that a collection date does not fall into multiple visitwindows. If a subject has two or more actual visits in one visit window,the visit closest to the target day will be used for analysis. If twovisits are equidistant from the target day, then the later visit will beused for analysis.

Statistical Analyses

The planned sample size of 170 for this study (with 1:1 randomisationratio) was determined to provide ≥90% power for detecting a 26%difference in ASAS40 response rate (assuming a placebo ASAS40 responserate of 20%). Power and sample size calculations were performed at atwo-sided significance level of 0.05 accounting for a 10% dropout rate.The full analysis set included all randomised patients who received atleast one dose of study drug. The safety analysis set included allpatients who received at least one dose of study drug. The SPARCC MRIassessment population was pre-specified in the statistical analysis plan(baseline included MRI data ≤3 days after first dose of study drug, andweek 14 included MRI data up to first dose of Period 2 study drug; firstdose in Period 2 was at week 14). A supplemental post hoc SPARCC MRIanalysis was conducted to include all MRI data collected at nominalvisits at baseline and week 14. Cumulative probability plots weregenerated to illustrate MRI SPARCC score changes on a patient level.

In the full analysis set, the primary endpoint was compared between theupadacitinib and the placebo group using the Cochran-Mantel-Haenszeltest, adjusting for the stratification factor of screening hsCRP level.Non-responder imputation was used for handling missing data. Similaranalyses as for the primary endpoint were conducted for secondaryefficacy binary endpoints. For continuous secondary efficacy endpoints,comparisons between the upadacitinib and the placebo group wereperformed using mixed model for repeated measures with treatment group,visit, and treatment-by-visit interaction as fixed effects and thecorresponding baseline value and the stratification factor of screeninghsCRP level as the covariates. In order to preserve the overall type Ierror rate at α=0.05 level, a step-down approach was used to test theprimary and multiplicity-controlled key secondary endpoints. The testingsequence includes a group of endpoints tested by the Hochberg procedure,including BASDAI50, ASQoL, ASAS PR, BASFI, BASMI, MASES, and WPAI (FIG.2 ). See, e.g., Hochberg Y, Tamhane A C. Multiple comparison procedures:John Wiley & Sons, Inc., 1987.

Week 14 Results

Between Oct. 24, 2017, and Sep. 10, 2018, 395 patients were assessed foreligibility, and 187 were enrolled into the study. Of the 395 patientsscreened, 208 (52.7%) did not meet eligibility criteria and wereexcluded from the study (main reason for screening failure was notmeeting the radiographic criterion of the modified New York criteria forAS). The remaining 187 patients who met eligibility criteria wererandomised to placebo (n=94) or upadacitinib (n=93). Overall, 95.2% ofpatients completed Period 1 through week 14 on study drug (placebo,89/94 [94.7%]; upadacitinib, 89/93 [95.7%]); one patient in the placebogroup discontinued study drug but completed Period 1 visits. The mostcommon primary reason for study drug discontinuation by week 14 wereadverse events in the placebo group (n=3 [3.2%]) and adverse events (n=2[2.2%]) and withdrawal of consent (n=2 [2.2%]) in the upadacitinibgroup.

Mean age was 45.4 years, mean duration from onset of symptoms was 14.4years, and mean duration since diagnosis was 6.9 years. Most patientswere male (132 [70.6%]), were human leukocyte antigen (HLA) B27 positive(143 [76.5%]) and were receiving concomitant NSAIDs at baseline (150[80.2%]). Baseline disease characteristics were generally balancedbetween the two groups. Key demographics and baseline characteristics ofthe patients are summarized in the below Table 19B.

TABLE 19B Key demographics and baseline characteristics of patients KeyDemographic and Upadacitinib Baseline Characteristics PLACEBO 15 mg qdMean (SD) or n (%) N = 94 n = 93 Male 69 (73.4) 63 (67.7) Age (Yrs) 44(12.1) 47 (12.8) HLA-B27 Positive 73 (77.7) 70 (75.3) White 76 (80.9) 79(84.9) Region North America 10 (10.6) 9 (9.7) South/Central America 0 0Western Europe 33 (35.1) 30 (32.3) Eastern Europe 34 (36.2) 36 (38.7)Asia^(a) 14 (14.9) 12 (12.9) Other^(b) 3 (3.2) 6 (6.5) Duration of ASDiagnosis (Yrs) 6.0 (6.79) 7.8 (10.64) Duration of AS Symptom (Yrs) 14.0(9.86) 14.8 (11.64) NSAID Use at Baseline 80 (85.1) 70 (75.3) PriorNSAID Use 94 (100) 92 (98.9) csDMARDs Use at Baseline 17 (18.1) 13(14.0) BASDAI 6.5 (1.56) 6.3 (1.76) Total back pain (NRS 0-10) 6.7(1.78) 6.8 (1.77) Patient Global Assessment 6.8 (1.66) 6.6 (1.81) (NRS0-10) ASDAS(CRP) 3.7 (0.74) 3.5 (0.76) BASFI (Function) 5.5 (2.17) 5.4(2.36) BASMI (Mobility) 3.5 (1.48) 3.7 (1.45) Presence of Enthesitis 55(58.5) 54 (58.1) (MASES > 0) MASES Score^(c) 3.7 (2.71) 3.9 (2.79) MRISpine SPARCC^(d) 11.9 (14.52) 10.4 (14.36) MRI Sacroiliac JointSPARCC^(d) 5.4 (8.55) 7.9 (10.91) hsCRP at Screening (mg/L) 11.7 (11.11)9.6 (12.57) hsCRP > ULN at Screening 68 (72.3) 67 (72.0) AS QoL 10.3(4.65) 10.0 (5.27) WPAI - Overall Work Impairment^(e) 53.3 (24.64) 54.3(28.10) ASAS Health Index 8.2 (3.84) 8.6 (4.12) ^(a)South Korea andJapan. ^(b)New Zealand and Australia. ^(c)Summarized for subjects withpresence of enthesitis at baseline. ^(d)Summarized for subjects whosebaseline MRI data up to 3 days post first dose of study drug.^(e)Summarized for subjects employed at baseline.

The study met its primary endpoint, with statistically significantlymore patients treated with upadacitinib versus placebo achieving ASAS40response at week 14 (48/93 [51.6%] vs 24/94 [25.5%]; p=0.0003) with atreatment difference (95% CI) of 26.1% (12.6-39.5%) (FIG. 3A). Asignificant difference for upadacitinib versus placebo in ASAS40 (FIG.13A) and the mean change for each of its four individual domains (FIGS.3B-3E) was observed as early as the first post-baseline visit (week 2),and this difference was maintained consistently through week 14, withweek 14 achieving a statistically significant difference in themultiplicity-controlled analysis. Accounting for multiplicityadjustment, change from baseline to week 14 in ASDAS (CRP) (FIG. 3C),SPARCC MRI spine (FIG. 3B), and BASFI (FIG. 3C) and proportion ofpatients who achieved BASDAI50 (FIG. 3A) and ASAS PR (FIG. 3A) werestatistically significant for upadacitinib versus placebo. Upadacitinibversus placebo mean (95% CI) change from baseline to week 14 was −1.45(−1.62 to −1.28) versus −0.54 (−0.71 to −0.37; treatment difference,−0.91 [−1.14 to −0.68; p<0.0001]) for ASDAS (CRP) and −2.29 (−2.73 to−1.85) versus −1.30 (−1.74 to −0.86; treatment difference, −1.00 [−1.60to −0.39; p=0.0013]) for BASFI. BASDAI50 was achieved by 42/93 (45.2%)patients treated with upadacitinib versus 22/94 (23.4%) patients in theplacebo group (treatment difference, 21.8% [8.5-35.0%; p=0.0016]) andASAS PR was achieved by 18/93 (19.4%) patients in the upadacitinib groupversus 1/94 (1.1%) in the placebo group (treatment difference, 18.3%[10.0-26.6%; p<0.0001]).

For the other multiplicity-controlled key efficacy endpoints,statistical significance based on multiplicity adjustment was not metper the Hochberg procedure. Consistent improvement was observed inpatients receiving upadacitinib versus placebo with nominal p values<0.05 for MASES (p=0.0488), BASMI (p=0.0296), ASQoL (p=0.0156), and ASASHI (p=0.0073) at week 14, except for WPAI (FIG. 3C).

The additional key secondary efficacy endpoints, ASAS20 and SPARCC MRISI joint score, also improved with upadacitinib versus placebo based onnominal p values (FIGS. 3A and 3B). ASAS20 was achieved by 60/93 (64.5%)patients treated with upadacitinib versus 38/94 (40.4%) of patients inthe placebo group at week 14 (treatment difference, 24.1% [10.2-38.0%;p=0.0010]).

For the SPARCC MRI outcomes, change from baseline to week 14 in SPARCCMRI spine was −6.93 (−8.58 to −5.28) for upadacitinib versus −0.22(−2.01 to 1.57) for placebo (treatment difference, −6.71 [−9.01 to−4.41; significant in multiplicity-controlled analysis, p<0.0001]) andchange from baseline to week 14 in SPARCC MRI SI joint was −3.91 (−5.05to −2.77) for upadacitinib versus −0.22 (−1.47 to −1.04) for placebo(treatment difference, −3.69 [−5.31 to −2.08; p<0.0001]; FIG. 3B). Thesupplemental MRI analysis conducted in all patients with available dataconfirmed the results of the primary SPARCC MRI analysis for both thespine and SI joints (FIG. 5 ). The cumulative probability plots ofchange in SPARCC scores demonstrated that SPARCC MRI spine and SI jointscores improved from baseline to week 14 to a greater extent in patientsreceiving upadacitinib compared with placebo; results for the primaryMRI analyses (FIG. 6A-6B) and supplemental MRI analyses (FIG. 6C-6D)were consistent. Table 19C below summarizes the primary and keysecondary efficacy endpoints at Week 14. Table 19D below providesadditional efficacy measurements at Week 14.

TABLE 19C Primary and Key Secondary Efficacy Endpoints at Week 14^(a)Upadacitinib PLACEBO 15 mg qd Endpoint N = 94 N = 93 Primary ASAS4025.5% 51.6% Multiplicity ASDAS(CRP) −0.54 −1.45 Adjusted Key MRI SpineSPARCC^(b) −0.22 −6.93 Secondary BASDAI50 23.4% 45.2% AS QoL −2.7 −4.2ASAS Partial 1.1% 19.4% Remission BASFI (Function) −1.30 −2.29 BASMI(Mobility) −0.1 −0.4 MASES (Enthesitis)^(c) −1.4 −2.3 WPAI - OverallWork −12.6 −18.1 Impairment^(d) ASAS Health Index −1.4 −2.8 Other KeyASAS20 40.4% 64.5% Secondary MRI SI Joints −0.22 −3.91 SPARCC^(c)^(a)Results for binary endpoints are based on NRI analysis. Analyses forall continuous endpoints are for the change from baseline value. Resultsfor continuous endpoints are based on MMRM or ANCOVA analysis.^(b)Summarized for subjects whose baseline MRI data up to 3 days postfirst dose of study drug and week 14 data up to the first dose of period2 study drug. ^(c)Summarized for subjects with presence of enthesitis atbaseline. ^(d)Summarized for subjects employed at baseline.

The proportions of patients who achieved ASDAS LDA, ASDAS ID, ASDAS CII,and ASDAS MI were greater (nominal p<0.0001) for upadacitinib versusplacebo at week 14 (FIG. 7A). These results are summarized in the belowTable 19D. Improvement in the mean ASDAS (FIG. 7B) and the individualASDAS components (FIGS. 8A-8D) was seen as early as week 2 withcontinued improvement up to week 14 with upadacitinib.

TABLE 19D Additional Efficacy Measurements at Week 14 UpadacitinibPLACEBO 15 mg qd Endpoint (N = 94) (N = 93) ASDAS ID   0% 16.1% ASDASLDA^(a) 10.6% 49.5% ASDAS MI  5.3% 32.3% ASDAS CII 18.1% 52.7%^(a)post-hoc analysis

Patients treated with the upadacitinib 15 mg QD dose showed greaterimprovement in back pain as assessed by the Total Back Pain component ofASAS response compared to placebo at Week 14. Improvement in the overalllevel of neck, back, or hip pain was demonstrated using BASDAI Question2. Improvements were also demonstrated for peripheral pain and swelling(assessed by BASDAI question 3 on overall pain in joints other than inthe neck, back, or hips) and nocturnal back pain. Improvements in totaland nocturnal back pain were observed as early as Week 2.

No serious infections, herpes zoster, malignancy, venous thromboembolicevents, or deaths were reported in Period 1. The proportion of patientswith adverse events was higher in the upadacitinib group 58/93 (62.4%)versus placebo group 52/94 (55.3%). One serious adverse event in eachgroup was reported during Period 1: cardiovascular disorder/circulationdysregulation in the placebo group (patient was not feeling well and washospitalised but no significant findings were obtained) and worsening ofspinal osteoarthritis in the upadacitinib group in a patient with ahistory of spondylosis and disc protrusion in the cervical spine. Theproportion of patients with adverse events leading to discontinuation ofstudy drug (upadacitinib, 2/93 [2.2%]; placebo, 3/94 [3.2%]) andinfections (upadacitinib, 19/93 [20.4%]; placebo, 26/94 [27.7%]) wassimilar for both treatment groups. The most common adverse event inpatients in the upadacitinib group was blood creatine phosphokinase(CPK), which increased (8/93 [8.6%] vs 2/94 [2.1%] patients in theplacebo group), with four events (vs one with placebo) assessed by theinvestigator to be possibly related to study drug; all patients wereasymptomatic with elevations <4×ULN, except for one patient in theplacebo group with muscle pain and an increase to 4.3×ULN. Most of theseevents were reversible without study drug interruption (6/8 withupadacitinib, 1/2 with placebo). One patient in the upadacitinib groupwho already had grade 2 neutropenia at baseline experienced a mildadverse event of grade 2 neutropenia.

Seven patients reported hepatic disorder adverse events (upadacitinib,5/93 [5.4%]; placebo, 2/94 [2.1%]); none resulted in study drugdiscontinuation, and all were asymptomatic alanine aminotransferase oraspartate aminotransferase increases, with associated elevations <2×ULNin 6/7 and an elevation <3×ULN in the remaining patient. No differencesin mean haemoglobin levels were observed throughout the 14-week periodin either group.

Increases from baseline to week 14 in low-density lipoproteincholesterol (0.318 mmol/L) and high-density lipoprotein (HDL)cholesterol (0.263 mmol/L) were observed in the upadacitinib groupversus the placebo group (−0.083 and 0.010 mmol/L, respectively);however, no changes in the total cholesterol/HDL ratio were observed(upadacitinib, −0.071 mmol/L; placebo, −0.083 mmol/L).

Week 14 Results Discussion

The SELECT-AXIS 1 is the first clinical trial of upadacitinib in AS anddemonstrated consistent efficacy results supported bymultiplicity-controlled endpoints. The study met its primary endpoint ofASAS40 response at week 14 (51.6% vs 25.5%) as well as severalmultiplicity-controlled secondary endpoints reflecting statisticallysignificant improvement in disease activity (ASAS PR, BASDAI50, ASDAS),function (BASFI), and MRI outcomes (SPARCC MRI spine). The othermultiplicity-controlled secondary endpoints did not meet significance inthe multiplicity testing but demonstrated consistent improvements forASQoL, BASMI, MASES, and ASAS HI, with upadacitinib versus placebo(nominal p<0.05), with the exception of WPAI.

A rapid onset of response to upadacitinib free base 15 mg QD treatmentwas observed for ASAS40 and ASDAS composite scores and their individualdomains of disease activity (e.g., back pain, PtGA, morning stiffness,function, and serum markers of inflammation [hsCRP]), with responsesobserved as early as week 2 (first post-baseline visit) and consistentlymaintained through week 14. The results of upadacitinib on improving thesigns and symptoms of AS are further confirmed by a significantreduction of active inflammation on MRI for both the spine and the SIjoints.

In addition, outcomes related to clinically relevant treatment goals ofremission or low disease activity, such as ASDAS ID or LDA, were alsoachieved, with 50% of patients reaching ASDAS LDA (difference vsplacebo, 39%). See, e.g., Smolen et al., Ann Rheum Dis 2018; 77: 3-17.Of note, the placebo response rates for ASAS20 and ASAS40 in this studywere similar to rates observed in recent clinical studies of AS;differences in ASAS40 response with upadacitinib versus placebo werep<0.05 (based on nominal p values) as early as week 2 and maintainedthroughout 14 weeks. See e.g., van der Heijde et al., Ann Rheum Dis2017; 76: 1340-47; van der Heijde et al., Lancet 2018; 392: 2378-87; vander Heijde et al., Lancet 2018; 392: 2441-51; Landewe et al., Ann RheumDis 2014; 73: 39-47. Interestingly, mean changes from baseline to week14 in the MRI SPARCC scores for the spine and SI joints in the placebogroup were quite small.

The study results are in line with findings from two Phase 2/3 JAKinhibitor studies in patients with active AS. See, e.g., van der Heijdeet al., Ann Rheum Dis 2017; 76: 1340-47; van der Heijde et al., Lancet2018; 392: 2378-87. Together with these findings, the SELECT-AXIS 1results further support that JAK inhibitors could represent an effectivetreatment option for AS. Currently, only TNF-α and IL-17 inhibition havebeen proven to be effective in axSpA; but, these cytokines are notdirectly blocked by JAK inhibitors including upadacitinib. See, e.g.,Furst and Louie, Arthritis Res Ther 2019; 21: 135. However, emergingdata from upadacitinib RA studies suggest that selective inhibition ofJAK1 may result in the secondary inhibition of additional pathways thatdo not depend on JAK1 signalling, such as TNF-α and IL-12. See, e.g.,Sornasse et al., Ann Rheum Dis 2019; 78: 365-66. Also, otherJAK1-associated pathways, including IL-7 and IL-22, have been describedin preclinical studies, but further research is needed to evaluate themechanism of action of JAK inhibitors in axSpA. See, e.g., Veale et al.,Rheumatology (Oxford) 2019; 58: 197-205; Gracey et al., Ann Rheum Dis2016; 75: 2124-32.

The proportion of patients with adverse events was generally similar inthe upadacitinib and placebo groups, and no new safety findings wereobserved compared with previous upadacitinib phase 3 RA studies. See,e.g., Burmester et al., Lancet 2018; 391: 2503-12; Genovese et al.,Lancet 2018; 391: 2513-24; Fleischmann R, Pangan A L, Song I, et al.Upadacitinib versus placebo or adalimumab in patients with rheumatoidarthritis and an inadequate response to methotrexate: results of a phase3, double-blind, randomized controlled trial. Arthritis Rheumatol 2019;doi: 10.1002/art.41032. [Epub ahead of print]; Cohen et al., Ann RheumDis (2019) 78. No serious infections, malignancies, anaemia,lymphopenia, herpes zoster, renal dysfunction, adjudicated major adversecardiovascular events, venous thromboembolic events, or deaths werereported, and haemoglobin levels remained consistent throughout thestudy.

A higher proportion of patients in the upadacitinib group experiencedadverse events of CPK elevation, all of which were asymptomatic and mostwere mild and reversible without study drug interruption. One patient inthe placebo group experienced symptoms (muscle pain) in the setting ofelevated CPK and permanently discontinued study drug. In the twoprevious JAK inhibitor studies, elevations in CPK were also observed.See e.g., van der Heijde et al., Ann Rheum Dis 2017; 76: 1340-47; vander Heijde et al., Lancet 2018; 392: 2378-87. Additional data are neededto better understand the safety profile of upadacitinib in axSpA.

JAK inhibitors, such as upadacitinib, could help address the unmet needin axSpA treatment given that only approximately half of bDMARD-naivepatients achieve an ASAS40 response and even less achieve remission withTNF or IL-17 inhibitor treatment. See, e.g., Sieper et al., Ann RheumDis 2017; 76: 571-92; Deodhar et al., Arthritis Rheumatol 2019; 71:599-611; van der Heijde et al., Lancet 2018; 392: 2441-51; Landewe etal., Ann Rheum Dis 2014; 73: 39-47; Lie E et al., Ann Rheum Dis 2011;70: 157-63; Glintborg et al., Ann Rheum Dis 2013; 72: 1149-55.Furthermore, fewer patients are expected to achieve the treatment goalof sustained remission/LDA, and response rates are even lower inpatients with AS who have not responded to bDMARD therapy. See, e.g.,Sieper et al., Lancet 2017; 390: 73-84; Sieper et al., Ann Rheum Dis2017; 76: 571-92; Deodhar et al., Arthritis Rheumatol 2019; 71: 599-611.Furthermore, some patients with axSpA may not be eligible for or mighthave contraindications common to IL-17 and TNF inhibitor therapy, suchas allergic reactions and injection site pain, or specific to TNFinhibitors, such as congestive heart failure and concomitantdemyelinating disease. See, e.g., Cortese et al., Mult Scler RelatDisord 2019; 35: 193-95. The use of IL-17 inhibitors is also notrecommended for patients with concomitant inflammatory bowel disease.See, e.g., van der Heijde et al., Ann Rheum Dis 2017; 76: 978-91;Fragoulis et al., World J Gastroenterol 2019; 25: 2162-76. Becausepatients with AS are typically younger and may have more activelifestyles, a treatment option administered orally may be particularlyimportant in this patient population. See e.g., Alten et al., PatientPrefer Adherence 2016; 10: 2217-28. Considering these unmet needs, thefindings of the SELECT-AXIS 1 study, which demonstrated thatupadacitinib treatment effects are within the range observed withbDMARDs and other JAK inhibitors in AS, support further investigation ofupadacitinib for AS. See, e.g., Sieper et al., Ann Rheum Dis 2017; 76:571-92; Deodhar et al., Arthritis Rheumatol 2019; 71: 599-611; van derHeijde et al., Ann Rheum Dis 2017; 76: 1340-47; van der Heijde et al.,Lancet 2018; 392: 2378-87; van der Heijde et al., Lancet 2018; 392:2441-51; Landewe et al., Ann Rheum Dis 2014; 73: 39-47.

This study is not without limitations. The focus on patients with AS whowere bDMARD-naive allowed for a focused evaluation of benefit and riskin a homogeneous population, but the safety and efficacy of upadacitinibin patients with AS who are bDMARD-IR or in patients withnon-radiographic axSpA has not yet been evaluated, and further studiesare needed in these patient populations. Furthermore, only one dose ofupadacitinib was evaluated in this study, and thus there are no data toconfirm whether a higher dose could have resulted in greater efficacy.Lastly, only 14-week, short-term data are reported here, but thelong-term efficacy and safety of upadacitinib will be collected in theongoing SELECT-AXIS 1 extension period for up to 2 years.

In conclusion, oral upadacitinib free base 15 mg QD significantlyimproved disease activity, function, and MRI-detected axial inflammationin patients with active AS after 14 weeks of treatment. The incidence ofadverse events was similar with upadacitinib and placebo, and no newsafety signals were observed compared with previous studies in RA.Overall, these results support the further investigation of upadacitinibfor the treatment of AS/axSpA.

Year 1 Results

The phase 2/3 SELECT-AXIS 1 study included a randomized,placebo-controlled, 14-week period followed by 90-week open-labelextension; reported here are data through week 64.

The study enrolled adults (≥18 years) with active AS who had aninadequate response to ≥2 non-steroidal anti-inflammatory drugs therapy(or intolerance to or contraindication for NSAIDs) and were biologicdisease-modifying antirheumatic drugs naïve, and who met the modifiedNew York criteria based on independent central reading of radiographs ofthe sacroiliac joints and who had active disease at baseline defined asBath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥4 andpatient's assessment of back pain score ≥4 (numeric rating scale [NRS],0-10) at screening and baseline visit. Patients receiving a stable doseof concomitant conventional synthetic disease-modifying antirheumaticdrugs (DMARDs), oral glucocorticoids, NSAIDs and analgesics wereeligible; patients with prior exposure to JAK inhibitors or biologicDMARDs with potential impact on spondyloarthritis were excluded. Of the187 patients randomized to Period 1, 178 (continuous upadacitinib, n=89;placebo switch, n=89) completed week 14 on study drug and entered theopen-label extension; 160 patients (continuous upadacitinib n=78[83.9%]; placebo switch, n=82 [87.2%]) completed week 64. Lack ofefficacy (n=10) and AEs (n=4) were the most common reasons fordiscontinuation of study drug between weeks 14 and 64. In the continuousupadacitinib and the placebo-to-upadacitinib switch groups, meanduration since AS symptom onset was 14.8 and 14.0 years, mean durationsince diagnosis was 7.8 and 6.0 years, mean ASDAS was 3.5 and 3.7, andmean hsCRP levels were 9.6 and 11.4 mg/L, respectively. Concomitantmedications included NSAIDs (76% and 86%), conventional synthetic DMARDs(14% and 18%), and glucocorticoids (6% and 13%, respectively).

Efficacy was assessed based on percentage of patients achieving ASAS20response, ASAS40 response, ASAS partial remission, BASDAI50, andAnkylosing Spondylitis Disease Activity Score (ASDAS) inactive disease(ID; <1.3), low disease activity (LDA; <2.1), major improvement (MI;decrease from baseline ≥2.0), and clinically important improvement (CII;decrease from baseline ≥1.1) through 64 weeks. In addition, change frombaseline in ASDAS based on C-reactive protein (ASDAS-CRP), BathAnkylosing Spondylitis Functional Index (BASFI), and linear BathAnkylosing Spondylitis Metrology Index (BASMI) through 64 weeks andMaastricht Ankylosing Spondylitis Enthesitis Score (MASES), WorkProductivity and Activity Impairment (WPAI; on a scale of 0-100), ASASHealth Index (HI), and AS quality of life (ASQoL) through 52 wereassessed.

ASAS20 and ASAS40 responses were defined as ≥20% or ≥40% improvement andan absolute improvement of ≥1 or ≥2 units (on an NRS scale of 0-10),respectively, from baseline in ≥3 of the following 4 domains (with noworsening of ≥20% and ≥1 unit or no worsening at all, respectively, inthe remaining domain): Patient Global Assessment of disease activity(PtGA), patient assessment of back pain, BASFI, and inflammation definedas the mean of BASDAI questions 5 and 6 (severity and duration ofmorning stiffness). ASAS partial remission was defined as an absolutescore of ≤2 units for each of the 4 domains identified for ASAS40response. ASDAS-CRP consists of patient-reported outcomes about backpain (BASDAI item 2), peripheral pain/swelling (BASDAI item 3), durationof morning stiffness (BASDAI item 6), the PtGA, and CRP.

The percentage of patients achieving the primary efficacy endpoint ofASAS40 at week 14 continued to increase throughout the study in thecontinuous upadacitinib group: 85% (95% CI, 77%-93%) of patientsachieved ASAS40 at week 64 in the as-observed analysis and 72% (63%-81%)in the NRI analysis (FIG. 3D). An analogous pattern of improvement wasobserved in the ASAS20 (94% [88%-99%] as-observed analysis and 80%[71%-88%] NRI analysis) (FIG. 3E), ASAS partial remission (46% [35%-57%]as-observed analysis and 40% [30%-50%] NRI analysis) (FIG. 3F), andBASDAI50 endpoints (82% [74%-91%] as-observed analysis and 70% [61%-79%]NRI analysis) (FIG. 3G). Patients who switched from placebo toupadacitinib at week 14 showed a speed of onset and magnitude ofresponses comparable with patients who were initially randomized toupadacitinib (responses at week 64 were ASAS40: 81% [72%-89%]as-observed analysis and 70% [61%-80%] NRI analysis; ASAS20: 96%[92%-100%] as-observed analysis and 83% [75%-91%] NRI analysis; ASASpartial remission: 39%[29%-50%] as-observed analysis and 34% [25%-44%]NRI analysis; and BASDAI50: (77% [68%-86%] as-observed analysis and 67%[58%-77%] NRI analysis). Likewise, the percentage of patients achievingASDAS ID (FIG. 3H), ASDAS LDA (FIG. 3I), ASDAS MI (FIG. 3J), and ASDASCII (FIG. 3K) continued to improve throughout the study in thecontinuous upadacitinib group; patients who switched to upadacitinibfrom placebo at week 14 showed a rapid onset of response for thesesendpoints, with responses at week 64 similar to those observed inpatients on continuous upadacitinib.

Mean changes from baseline to 1 year in disease activity (ASDAS),physical function (BASFI), patient assessment of pain and diseaseactivity (PtGA), and inflammation (hsCRP) showed consistent improvementor sustained maintenance throughout the study in the continuousupadacitinib group; a similar magnitude of improvement was seen in theplacebo-to-upadacitinib switch group after initiation of upadacitinib atweek 14. Analogous patterns of improvement were shown in assessments ofquality of life (ASQoL and ASAS HI), spinal mobility (BASMI), andenthesitis (MASES) over time, as well as in measurements of back pain,nocturnal back pain, BASDAI Q2 (back pain) and BASDAI Q5/6. Amongpatients who were employed at baseline, the mean (95% CI) WPAI overallwork impairment score continued to improve throughout the study in thecontinuous upadacitinib group (from −20.5 [−27.1, −14.0] at week 14 to−35.6 [−43.2, −28.0] at week 52; as-observed analysis) andplacebo-to-upadacitinib switch group (from −12.3 [−19.8, −4.8] at week14 to −27.7 [−35.4, −20.0] at week 52).

A significantly higher proportion of patients receiving upadacitinibversus placebo achieved ≥30% and ≥50% reduction in Patient's GlobalAssessment (PGA) of pain and back pain as early as week 2, and ≥70%reduction as early as week 4, and efficacy achieved was sustainedthereafter. See, e.g., FIGS. 3L-3N. Patients who switched from placeboto open-label upadacitinib at week 14 generally reached the same levelof pain reduction after week 14 as those initially randomized toupadacitinib.

Upadacitinib as a Promising Oral Therapy in AS and nr-AxSpA

SELECT-AXIS 1, the first study to report long-term data with a JAKinhibitor in AS, showed that upadacitinib 15 mg QD therapy led tosustained and consistent efficacy up to and including Week 64 in bothNRI and as-observed analyses in patients with active AS who had aninadequate response to NSAIDs. Improvements were seen in diseaseactivity measures (ASDAS, BASDAI, ASAS, and their components),inflammation (hsCRP), physical function (BASFI), quality of life (ASQoL,ASAS HI), and other aspects of disease (BASMI, MASES) with continuousupadacitinib therapy. In patients who switched from placebo toupadacitinib at week 14, a similar speed of onset and magnitude ofefficacy response was observed up to and including Week 64 compared withthose who received continuous upadacitinib starting at Week 0. Of note,approximately 40%-45% of patients receiving upadacitinib reachedremission based on the more difficult to achieve endpoints ASAS partialremission (PR) or ASDAS inactive disease (ID) up to and including Week64, and >80% were in a state of ASDAS low disease activity (LDA).

The below Table 19E provides placebo corrected data for upadacitinib atWeek 14, biologics Ixekizumab and Adalimumab at Week 16, and JAK smallmolecule inhibitors Tofacitinib and Filgotinib at Week 12 for keyprimary and secondary endpoints. While this data is not a head to headcomparison, the placebo corrected response calculated for upadacitinibfor the more difficult to achieve endpoints ASAS PR, ASDAS ID, and ASDASLDA shows decided promise over the efficacy demonstrated by the othertwo JAK small molecule inhibitors, with a remarkable efficacy onlycomparable to that demonstrated with the biologics. Furthermore, thisefficacy, once achieved at Week 14, was sustained or improved over time,with long term efficacy in these difficult to achieve endpoints(including ASDAS major improvement (MI) and ASDAS clinically importantimprovement (CII)), sustained or improved up to and including Week 64.Coupled with the fact that upadacitinib is well tolerated with no new orunexpected safety findings (particularly compared to the other JAKinhibitors), the data suggests upadacitinib will be a promising new safeoral therapy for AS patients, especially for those AS patients who haveactive disease and inadequate response to NSAIDs.

TABLE 19E Placebo Corrected Responses (% response/placebo response, pvalue) Ixekizumab vs. Adalimumab H2H Study ADA 40 mg TofacitinibUpadacitinib Ixekizumab EOW 5 mg BID Filgotinib 15 mg QD Q4W Week 16Week 12 200 mg QD Week 14 Week 16 (TNF (bDMARD- Week 12 Endpoint(naiive) (TNF naiive) naiive) naiive) (Mixed) ASAS20 24.1% 24% 19% 39.6%36.2% (64.5%/40.4%, (64%/40%, (59%/40%, (80.8%/41.2%, (75.9%/39.7%, p <0.001) p = 0.0015) p = 0.0075) p ≤ 0.001) p < 0.0001) ASAS40 26.1% 30%18% 26.6% 18.9% (51.6%/25.5%, (48%/18%, (36%/18%, (46.2%/19.6%,(37.9%/19%, p < 0.001*) p < 0.0001,) p = 0.0053) p ≤ 0.01) p = 0.0189)BASDAI50 21.8% 25% 15% 18.8% NA (45.2%/23.4%, (42%/17%, (32%/17%,(42.3%/23.5%, p = 0.002*) p = 0.0003) p = 0.0119) p ≤ 0.05) ASAS 18.3%NA NA 7.4% 8.7% Partial (19.4%/1.1%, (19.2%/11.8%, (12.1%/3.4%, Remisson(PR) p < 0.001*) NS) p = 0.1028) ASDAS 16.1% 14% 14% 5.7% 5% InactiveDisease (16.1%/0%, (16%/2%, (16%/2%. (13.5%/7.8%. (5%/0%, (ID) p <0.001) p = 0.0074) p = 0.0087) NS) p = 0.092) ASDAS 38.9% 30% 25% 34.3%NA low disease (49.5%/10.6%, (43%/13%, (38%/13%, (53.9%/19.6%, activity(LDA) p < 0.001) p < 0.0001) p = 0.0002) p ≤ 0.001) NS: non-significant;NA: not available; UPA p values are nominal, unless *significant aftermultiplicity-adjustment; Ixekizumab bDMARD-naïve AS COAST-V Study. Vander Heijde et al. Lancet 2018; 392: 2441-51; Tofacitinib study: van derHeijde D, et al. ARD 2017; 0: 1-8.; Filgotinib study: van der Heijde etal. Lancet 2018; 392: 2378-87.

Example 32. A Phase 3 Randomized, Placebo-Controlled, Double-BlindProgram to Evaluate Efficacy and Safety of Upadacitinib in AdultSubjects with Axial Spondyloarthritis Followed by a Remission-WithdrawalPeriod (SELECT AXIS 2) (Study 1)

The safety and efficacy data from the Phase 2/3 study (as described inU.S. Pat. App. No. 2021/0228575) show a favorable benefit:risk profilefor upadacitinib and support the continued investigation of upadacitinibin adult subjects with active axSpA who had an inadequate response tobiologic disease-modifying anti-rheumatic drug therapy (bDMARD-IR)(Study 1; Example 32) and in adult subjects with active nr-axSpA (Study2; Example 33). The Phase 3 clinical study plan is set forth in FIG. 9 .

Adult Subjects with Active Ankylosing Spondylitis (AS) Who had anInadequate Response to Biologic Disease-Modifying Anti-Rheumatic DrugTherapy (bDMARD-IR) (Study 1)

Study 1 is a Phase 3, randomized, placebo-controlled, double-blindmulticenter study to evaluate the safety, tolerability, and efficacy ofupadacitinib compared with placebo on reduction of signs and symptoms inadult subjects with active ankylosing spondylitis (AS) who had aninadequate response to biologic disease-modifying anti-rheumatic drugtherapy (bDMARD-IR).

Study 1 (main study) is comprised of a 35-day Screening Period; a14-week randomized, double-blind, parallel-group, placebo-controlledperiod (the Double-Blind Period) designed to compare the safety andefficacy of upadacitinib freebase 15 mg QD versus placebo for thetreatment of signs and symptoms of subjects with active AS who have aninadequate response to bDMARD therapy; and a 90-week open-label,long-term extension period (the Open-Label Extension Period) to evaluatethe long-term safety, tolerability, and efficacy of upadacitinib freebase 15 mg QD in subjects who have completed the Double-Blind Period upto Week 104 (see FIG. 9 ).

Subjects in Study 1 who reach Week 104 on study drug (upadacitinib freebase 15 mg QD) will be assessed whether they are in remission. Subjectsin remission at Week 104 will be eligible for the Remission-WithdrawalPeriod. Subjects will be followed without study drug treatment andassessed for disease flare through Week 152. Subjects who flare willreceive open-label upadacitinib free base 15 mg QD from the time offlare for 24 weeks (re-treatment) or longer.

Subjects were enrolled from 119 sites in 22 countries. Eligible subjectswere adult females and males who were at least 18 years of age atScreening with a clinical diagnosis of AS, met the modified New YorkCriteria for AS, and were without total spinal ankylosis. Eligible studysubjects must have had a Bath Ankylosing Spondylitis Disease ActivityIndex score ≥4 and a Patient's Assessment of Total Back Pain score(Total Back Pain score) ≥4 based on a 0-10 numerical rating scale at theScreening and Baseline Visits.

Subjects were randomized in a 1:1 ratio to one of two treatment groups,stratified by screening hsCRP (≤ULN vs >ULN), the class of prior bDMARDuse (1 TNF, 1 IL-17, other) and geographic region:

-   -   Group 1: Upadacitinib free base 15 mg QD (N=211) (Double-Blind        Period)→Upadacitinib free base 15 mg QD (Open-Label Period)    -   Group 2: Placebo (N=209) (Double-Blind Period)→Upadacitinib free        base 15 mg QD (Open-Label Period)        Study 1 Primary Endpoint

The primary endpoint was the proportion of subjects achieving an ASAS40response at Week 14. Secondary endpoints for Study 1 are describedbelow.

Study 1: bDMARD-IR AS Specific Criteria

-   -   1. Subject must have a clinical diagnosis of AS and subjects        must meet the modified New York criteria for AS.    -   2. Subject must not have total spinal ankylosis.    -   3. Subjects with prior exposure to 1 bDMARD (either 1 tumor        necrosis factor [TNF] inhibitor or 1 interleukin [IL]-17        inhibitor) may be enrolled, and the subject must have        discontinued the bDMARD due to either intolerance or lack of        efficacy. Prior exposure to a 2^(nd) bDMARD was allowed for no        more than 30% of subjects if the reason for discontinuation was        not due to lack of efficacy. Subjects who have had lack of        efficacy to both a TNF inhibitor and IL-17 inhibitor were not        eligible.        Study 1 Eligibility Criteria:    -   1. Subject must be an adult male or female, at least 18 years of        age at Screening.    -   2. Subject must meet the following scores at Screening and        Baseline Visits: BASDAI score ≥4 and Total Back Pain score ≥4        based on a 0-10 NRS.    -   3. Subject has had an inadequate response to at least 2 NSAIDs        over an at least 4-week period in total at maximum recommended        or tolerated doses, or subject has an intolerance to or        contraindication for NSAIDs.    -   4. The washout period for bDMARDs prior to the first dose of        study drug is specified below:        -   ≥4 weeks for etanercept;        -   ≥8 weeks for adalimumab, infliximab, certolizumab,            golimumab, abatacept, tocilizumab, and ixekizumab;        -   ≥12 weeks for ustekinumab;        -   ≥16 weeks for secukinumab;        -   ≥1 year for rituximab OR ≥6 months if B cells have returned            to pre-treatment level or normal reference range (central            lab) if pre-treatment levels are not available;        -   ≥12 weeks or at least 5 times the mean terminal elimination            half-life, whichever is longer, for other bDMARDs.    -   5. If entering the study on the following concomitant csDMARDs        (MTX (≤25 mg/week); or Sulfasalazine (SSZ) 3 g/day); or        Hydroxychloroquine (≤400 mg/day); or Chloroquine (≤400 mg/day);        or Leflunomide (≤20 mg/day); or Apremilast 60 mg/day)), subject        must be on a stable dose as indicated below for at least 28 days        prior to the Baseline Visit. A combination of up to 2 background        csDMARDs is allowed EXCEPT the combination of methotrexate (MTX)        and leflunomide.    -   6. If entering the study on concomitant oral corticosteroids,        subject must be on a stable dose of prednisone (≤10 mg/day) or        oral corticosteroid equivalent for at least 14 days prior to the        Baseline Visit.    -   7. If entering the study on concomitant NSAIDs, tramadol,        combination of acetaminophen/paracetamol and codeine or        combination of acetaminophen/paracetamol and hydrocodone, and/or        non-opioid analgesics, subject must be on stable dose(s) for at        least 14 days prior to the Baseline Visit.    -   8. Subject must not have been exposed to any JAK inhibitor.    -   9. Subject must not have used the following prohibited        concomitant treatments within the specified timeframe prior to        Baseline Visit:        -   Intra-articular joint injections, spinal/paraspinal            injection(s), or parenteral administration of            corticosteroids within 28 days prior to the Baseline Visit.            Inhaled or topical corticosteroids are allowed;        -   Any other csDMARDs (other than those allowed per eligibility            criterion), including thalidomide, within 28 days or 5            half-lives (whichever is longer) of the drug prior to the            Baseline Visit;        -   Opioid analgesics (except for combination of            acetaminophen/paracetamol and codeine or combination of            acetaminophen/paracetamol and hydrocodone which are allowed)            within 14 days prior to the Baseline Visit.    -   10. Subject must not have received a live vaccine within 28 days        (or longer if required locally) prior to the first dose of study        drug or have expected need of live vaccination during study        participation including at least 30 days (or longer if required        locally) after the last dose of study drug.    -   11. Subject must have no systemic use of known strong cytochrome        P450 3A (CYP3A) inhibitors from Screening through the end of        study drug administration or strong CYP3A inducers 30 days prior        to study drug administration through the end of study drug        administration. Subjects must not use herbal therapies or other        traditional medicines with unknown effects on CYP3A from        Screening through the end of study drug administration.    -   12. Subject must not have been treated with any investigational        drug of chemical or biologic nature within a minimum of 30 days        or 5 half-lives of the drug (whichever is longer) prior to the        first dose of study drug or is currently enrolled in another        interventional study.    -   13. Subject must not have a history of an allergic reaction or        significant sensitivity to constituents of the study drug (and        its excipients) and/or other products in the same class.        Study 1 Secondary Endpoints

The key multiplicity-controlled secondary endpoints at Week 14 are asfollows:

TABLE 20A Key multiplicity-controlled secondary endpoints at Week 14(Study 1) 1 Change from Baseline in Ankylosing Spondylitis DiseaseActivity Score (ASDAS) (CRP) 2 Change from Baseline in magneticresonance imaging (MRI) Spondyloarthritis Research Consortium of Canada(SPARCC) score (spine) (MRI-Spine SPARCC) 3 Proportion of subjects withBath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response4 Proportion of subjects with ASAS20 response 5 Proportion of subjectswith ASDAS (CRP) Inactive Disease (ASDAS score < 1.3) 6 Change fromBaseline in Patient's Assessment of Total Back Pain (Total Back Painscore) 7 Change from Baseline in Patient's Assessment of Nocturnal BackPain (Nocturnal Back Pain) 8 Proportion of subjects with ASDAS (CRP) LowDisease Activity (ASDAS score < 2.1) 9 Change from Baseline in BathAnkylosing Spondylitis Functional Index (BASFI) (Function) 10 Proportionof subjects with ASAS partial remission (PR) (an absolute score of ≤2units for each of the 4 domains identified in ASAS40) 11 Change fromBaseline in Ankylosing Spondylitis Quality of Life (ASQoL) 12 Changefrom Baseline in ASAS Health Index (HI) 13 Change from Baseline inLinear Bath Ankylosing Spondylitis Metrology Index (BASMI_(lin))(Mobility) 14 Change from Baseline in Maastricht Ankylosing SpondylitisEnthesitis Score (MASES) (Enthesitis)

Additional key secondary endpoints at Week 14 include: Change fromBaseline in MRI SPARCC score (SI joints).

Additional Study 1 Endpoints

Additional endpoints are the following measurements assessed at timepoints other than those specified for the primary and key secondaryvariables are as follows:

TABLE 20B Additional endpoints (Study 1) 1 Proportion of subjects withASAS20 response 2 Proportion of subjects with ASAS40 response 3Proportion of subjects with ASAS PR 4 Proportion of subjects with ASDASInactive Disease (ASDAS score <1.3) 5 Proportion of subjects with ASDASLow Disease (ASDAS score <2.1) 6 Proportion of subjects with ASDAS MajorImprovement (a change from Baseline of ≤−2.0) 7 Proportion of subjectswith ASDAS Clinically Important Improvement (a change from Baseline of≤−1.1) 8 Proportion of subjects with Discontinuation of opioids amongsubjects with opioid use at Baseline 9 Change from Baseline in ASAS HI10 Change from Baseline in ASDAS 11 Change from Baseline in ASQoL 12Change from Baseline in BASDAI and BASDAI Questions including mean ofquestion 5 and 6 of the BASDAI 13 Change from Baseline in BASFI 14Change from Baseline in BASMIlin 15 Change from Baseline in Highsensitivity C-reactive protein (hsCRP) 16 Change from Baseline inFunctional Assessment of Chronic Illness Therapy-Fatigue (FACIT- F) 17Change from Baseline in EuroQoL-5D-5L (EQ-5D-5L) 18 Change from Baselinein MASES 19 Change from Baseline in Modified Stoke AnkylosingSpondylitis Spine Score (mSASSS) with conventional radiograph 20 Changefrom Baseline in MRI SPARCC score of SI joints 21 Change from Baselinein MRI SPARCC score of spine 22 Change from Baseline in Patient'sAssessment of Total Back Pain (Total Back Pain Score) 23 Change fromBaseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal BackPain) 24 Change from Baseline in Patient's Global Assessment of Pain(Pain) 25 Change from Baseline in Physician's Global Assessment ofDisease Activity (PGA) 26 Change from Baseline in Patient's GlobalAssessment of Disease Activity (PtGA) 27 Change from Baseline in 36-ItemShort Form Health Survey (SF-36) 28 Change from Baseline in Tender jointcount (TJC) and swollen joint count (SJC); 29 Change from Baseline inWork Productivity and Activity Impairment (WPAI) 30 Change from Baselinein Change of NSAID score 31 Change from Baseline in Physical ActivityAssessment (step count, physical activity, and spinal range of motiontasks) as measured by a wearable device (in countries where the digitalhealth technology device is approved)

A total of 420 subjects were randomized in Study 1 and received doubleblind study drug treatment, out of which 409 (97.4%) completed studydrug through Week 14. The rates of premature discontinuation of studydrug were low and similar in the placebo group and the upadacitinibtreatment group (Table 20C). The key demographics and baselinecharacteristics were balanced across the treatment groups and generallyconsistent with the targeted patient population (Table 20D).

TABLE 20C Subject Disposition UPADACITINIB FREE BASE Subject DispositionPLACEBO 15 MG QD Randomized 209 211 Full Analysis Set (FAS) 209 211 PerProtocol Analysis Set 194 186 Safety Analysis Set 209 211 CompletedStudy Drug Through 203 (97.1) 206 (97.6) Week 14, n(%)^(b) PrematurelyDiscontinued 6 (2.9) 5 (2.4) Study Drug by Week 14^(a), n(%)^(b) AdverseEvents 3 (1.4) 0 Withdrew Consent 1 (0.5) 0 Lost To Follow-Up 1 (0.5) 1(0.5) Lack of Efficacy 1 (0.5) 1 (0.5) COVID-19 Infection 0 0 COVID-19Logistical Restrictions 0 1 (0.5) Other 0 2 (0.9) ^(a)Primary reasonsfor premature discontinuation of study drug are summarized.^(b)Percentage is calculated based upon the FAS.

TABLE 20D Key Demographics and Baseline Characteristics Key Demographicand Baseline UPADACITINIB Characteristics PLACEBO 15 MG QD Mean (SD) orn (%) N = 209 N = 211 Male 158 (75.6) 153 (72.5) Age (Yrs) 42.2 (11.78)42.6 (12.39) HLA-B27 Positive 168 (81.2) 180 (85.3) White 169 (80.9) 168(79.6) Region North America 25 (12.0) 25 (11.8) South/Central America 14(6.7) 13 (6.2) Western Europe 25 (12.0) 16 (7.6) Eastern Europe 98(46.9) 109 (51.7) Asia^(a) 34 (16.3) 41 (19.4) Other^(b) 13 (6.2) 7(3.3) Duration since AS Diagnosis (Yrs) 7.5 (7.51) 7.9 (7.54) Durationof AS Symptom (Yrs) 12.6 (9.29) 12.9 (9.08) NSAIDs Use at Baseline 163(78.0) 163 (77.3) Oral Corticosteroids Use at Baseline 18 (8.6) 27(12.8) csDMARDs Use at Baseline 62 (29.7) 68 (32.2) Prior bDMARD UseClass 1 TNF 158 (76.0) 154 (73.0) 1 IL-17 24 (11.5) 29 (13.7) 2 bDMARDsexposure 26 (12.5) 28 (13.3) BASDAI (0-10) (disease activity) 6.8 (1.26)6.8 (1.34) Total Back Pain (NRS 0-10) 7.4 (1.43) 7.5 (1.48) NocturnalBack Pain (NRS 0-10) 7.2 (1.50) 7.1 (1.77) Patient Global Assessment 7.2(1.40) 7.4 (1.48) (NRS 0-10) ASDAS(CRP) 3.9 (0.77) 3.9 (0.79) BASFI(Function) (0-10) 6.2 (1.87) 6.3 (2.03) BASMI (Mobility) 3.9 (1.55) 3.9(1.57) Presence of Enthesitis at baseline 162 (77.9) 148 (70.1) (MASES >0) MASES Score^(c) (0-13) 4.2 (3.13) 4.9 (2.99) MRI Spine SPARCC^(d)(0-108) 8.8 (12.52) 10.7 (15.43) MRI Sacroiliac Joint SPARCC^(d) 5.6(10.63) 5.0 (10.80) (0-72) hsCRP at Screening (mg/L) 14.5 (17.84) 15.8(17.69) hsCRP > ULN (2.87 mg/L) at 163 (78.0) 165 (78.2) Screening ASQoL (0-18) 11.5 (4.44) 11.6 (4.38) ASAS Health Index (0-17) 8.9 (3.75)9.4 (3.50) ^(a)China, Taiwan, South Korea and Japan. ^(b)New Zealand,Australia and Israel. ^(c)Summarized for subjects with presence ofenthesitis at baseline. ^(d)Summarized for subjects with availablebaseline MRI data up to 3 days post first dose of study drug.Efficacy

The primary endpoint was the achievement of ASAS40 response at Week 14.The primary analysis, using Non-Responder Imputaion in conjunction withMultiple Imputation (NRI-MI) to handle missing data due to COVID-19,showed a statistically significantly higher response rate (p<0.0001) inthe upadacitinib group (44.5%) as compared to placebo (18.2%) (FIG.10A). Sensitivity and supplementary analyses using NRI, As Observed (AO)data, and analyses on the Per Protocol population showed consistentresults.

All ranked secondary endpoints were statistically significant (allp<0.0001, Table 20E; FIGS. 11A-11F). FIG. 10B shows ASAS 40 responserate over time up to Week 14. Upadacitinib showed onset of effect inASAS40 as early as Week 4.

TABLE 20E Primary and Ranked Key Secondary Efficacy Endpoints at Week14^(a) UPADACITINIB PLACEBO 15 MG QD UPA − PBO Endpoint N = 209 N = 211(95% CI) P-VALUE^(b) Primary ASAS40 18.2% 44.5% 26.4 (17.9, 34.9)<0.0001* Ranked Key 1 ASDAS(CRP) −0.49 −1.52 −1.02 (−1.20, −0.85)<0.0001* Secondary 2 MRI Spine −0.04 −3.95 −3.90 (−5.47, −2.33) <0.0001*SPARCC^(c) 3 BASDAI50 16.7% 43.1% 26.4 (18.0, 34.8) <0.0001* 4 ASAS2038.3% 65.4% 27.1 (17.9, 36.3) <0.0001* 5 ASDAS(CRP) 1.9% 12.8% 10.9(6.0, 15.8) <0.0001* Inactive Disease 6 Total Back −1.47 −3.00 −1.53(−1.96, −1.11) <0.0001* Pain 7 Nocturnal Back −1.5 −3.2 −1.7 (−2.1,−1.2) <0.0001* Pain 8 ASDAS(CRP) 10.1% 44.1% 34.0 (26.2, 41.8) <0.0001*Low Disease Activity 9 BASFI −1.09 −2.26 −1.17 (−1.55, −0.80) <0.0001*(Function) 10 ASAS 4.3% 17.5% 13.2 (7.4, 19.0) <0.0001* PartialRemission 11 AS QoL −2.03 −5.10 −3.07 (−3.90, −2.24) <0.0001* 12 ASASHealth −1.07 −2.93 −1.85 (−2.47, −1.24) <0.0001* Index 13 BASMI −0.16−0.48 −0.32 (−0.46, −0.18) <0.0001* (Mobility) 14 MASES −1.1 −2.6 −1.5(−2.0, −0.9) <0.0001* (Enthesitis)^(d) ^(a)Results for binary endpointsare based on NRI-MI analysis. Analyses for all continuous endpoints arefor the change from baseline value. Results for continuous endpoints arebased on MMRM, except for MRI and BASMI which use ANCOVA analysis.^(b)Unadjusted p-values are presented. *Denotes multiplicity-controlledstatistical significance at the pre- specified two-sided 0.05 level.^(c)Summarized for subjects with available baseline MRI data up to 3days post first dose of study drug and available week 14 MRI data up tothe first dose of open-label period study drug. ^(d)Summarized forsubjects with presence of enthesitis at baseline (N = 162 in Placebo, N= 148 in UPA).Safety

In this Phase 3 AS bDMARD-IR study, the safety profile of upadacitinibfreebase was consistent with what is known for upadacitinib, and no newrisks were identified.

Adverse Events

The overview of TEAEs and AESIs up to Week 14 are summarized in Table20F and Table 20G respectively. The rate of overall AEs was similarbetween the upadacitinib freebase 15 mg and placebo groups. Up to Week14, there were no events of malignancy, adjudicated GI perforation,adjudicated MACE, or adjudicated VTE reported in subjects receivingupadacitinib freebase. There was one malignancy observed in the placebogroup. Serious AEs were reported more frequently with upadacitinibfreebase 15 mg, the majority of which were COVID-19 or COVID-19pneumonia. For AEs leading to discontinuation of study drug, none werereported with upadacitinib 15 mg compared to 3 (1.4%) with placebo. Nodeaths were reported.

Serious infections and herpes zoster were reported with upadacitinib 15mg (2.4% and 0.9%, respectively). Four of the 5 serious infections wereCOVID-19 or COVID-19 pneumonia. Both herpes zoster events werenonserious, did not lead to treatment discontinuation, and involved asingle dermatome.

One event of tonsil cancer was reported in a subject receiving placebo.No malignancy was reported with upadacitinib 15 mg.

All hepatic disorders reported in the upadacitinib group were mild ormoderate transaminase elevations; none were serious or led todiscontinuation of treatment.

AEs of anemia, neutropenia, and lymphopenia were generally mild ormoderate, nonserious, and did not lead to treatment discontinuation.

There were no events of opportunistic infection, non-melanoma skincancer, lymphoma, adjudicated GI perforation, renal dysfunction, activetuberculosis, adjudicated MACE or VTE reported.

More COVID-19 related infections were reported with upadacitinibcompared to placebo. None of the infections led to discontinuation ofstudy drug.

Through week 14, the most common adverse events (≥3% of patients) forRINVOQ were COVID-19 and headache. The proportion of patients withadverse events leading to discontinuation, serious adverse events andserious infections were 0 percent/2.8 percent/2.4 percent for RINVOQ and1.4 percent/0.5 percent/0 percent for placebo, respectively. Seriousinfections included four events of COVID-19 and one of uveitis withRINVOQ; two patients on RINVOQ developed non-serious, mild or moderateherpes zoster limited to one dermatome. One patient treated with placebodeveloped a malignancy (tonsil cancer). No adjudicated major adversecardiovascular events, venous thromboembolic events or deaths werereported in either group through week 14.

TABLE 20F Overview of Treatment-Emergent Adverse Events (TEAE) up toWeek 14 Upadacitinib Placebo 15 mg QD (N = 209) (N = 211) n (%) n (%)Adverse event (AE) 77 (36.8) 86 (40.8) AE with reasonable possibility ofbeing 25 (12.0) 36 (17.1) related to study treatment^($) Severe AE 8(3.8) 7 (3.3) Serious AE 1 (0.5) 6 (2.8) AE leading to withdrawal ofstudy 3 (1.4) 0 (0.0) treatment AE leading to death 0 (0.0) 0 (0.0)COVID-19 related AE# 6 (2.9) 12 (5.7)  All deaths 0 (0.0) 0 (0.0) ^($)Asassessed by investigator. #As collected in AE eCRF.

TABLE 20G Overview of Treatment-Emergent Adverse Events of SpecialInterest up to Week 14 Upadacitinib Placebo 15 mg QD (N = 209) (N = 211)n (%) n (%) Infection 27 (12.9) 31 (14.7) Serious infection 0 (0.0) 5(2.4) Opportunistic infection excluding 0 (0.0) 0 (0.0) tuberculosis andherpes zoster Herpes zoster 0 (0.0) 2 (0.9) Active tuberculosis 0 (0.0)0 (0.0) Malignancy 1 (0.5) 0 (0.0) Non-melanoma skin cancer 0 (0.0) 0(0.0) (NMSC) Malignancy other than NMSC 1 (0.5) 0 (0.0) Lymphoma 0 (0.0)0 (0.0) Hepatic disorder 2 (1.0) 6 (2.8) Adjudicated gastrointestinal 0(0.0) 0 (0.0) perforation Anemia 1 (0.5) 3 (1.4) Neutropenia 2 (1.0) 6(2.8) Lymphopenia 2 (1.0) 1 (0.5) Renal dysfunction 0 (0.0) 0 (0.0)Adjudicated MACE* 0 (0.0) 0 (0.0) Adjudicated venous 0 (0.0) 0 (0.0)thromboembolic events** *MACE; Major adverse cardiovascular events,defined as cardiovascular death (includes acute myocardial infarction,sudden cardiac death, heart failure, cardiovascular procedure-relateddeath, death due to cardiovascular hemorrhage, fatal stroke, pulmonaryembolism and other cardiovascular causes), non-fatal myocardialinfarction and non-fatal stroke. **VTE include deep vein thrombosis(DVT) and pulmonary embolism (PE) (fatal and non-fatal).Potentially Clinically Significant Lab Findings

Potentially clinically significant lab and vital sign abnormalities werereported infrequently (Table 20H). There was no Hy's law case in thisstudy up to Week 14.

TABLE 20H Potentially Clinically Significant Labs in Double-Blind Period(Week 14) UPADACITINIB Lab Parameter^(a) PLACEBO 15 MG QD n/N_obs (%) N= 209 N =211 Hemoglobin (g/L) Grade 3 (<80) 0/209 0/211 Lymphocytes(10{circumflex over ( )}9/L) Grade 3 (0.2-<0.5) 0/209 1/211 (0.5) Grade4 (<0.2) 0/209 0/211 Neutrophils (10{circumflex over ( )}9/L) Grade 3(0.5-<1.0) 1/209 (0.5) 4/211 (1.9) Grade 4 (<0.5) 0/209 0/211 ALT (U/L)Grade 3 (>5.0-20.0 xULN) 1/209 (0.5) 1/211 (0.5) Grade 4 (>20.0 xULN)0/209 0/211 AST (U/L) Grade 3 (>5.0-20.0 xULN) 2/209 (1.0) 2/211 (0.9)Grade 4 (>20.0 xULN) 0/209 0/211 Creatinine (umol/L) Grade 3 (>3.0-6.0xULN 2/209(1.0) 0/211 or >3.0 × Baseline) Grade 4 (>6.0 xULN) 0/2090/211 ^(a)Grading is based CTCAE V4 criteria; Grade must be worse thanthe baseline grade to be countedDiscussion

Overall, the results from Study 1 support planned regulatory submissionsin the AS indication. In bDMARD-IR population, upadacitinib demonstratedsignificantly greater improvements in AS signs and symptoms of AS,including back pain and inflammation, as well as improvements inphysical function, disease activity, mobility, and quality of lifecompared to placebo at Week 14.

Additionally, significantly more patients treated with the upadacitinibfreebase 15 mg QD achieved ASDAS Low Disease Activity (LDA) compared tothose treated with placebo (44 percent versus 10 percent). Astatistically significantly greater improvement in Magnetic ResonanceImaging (MRI) Spondyloarthritis Research Consortium of Canada (SPARCC)Score (Spine) as measured by mean change from baseline was reported inthe treatment group versus the placebo group (−3.95 versus −0.04).Patients in the treatment group experienced a significantly greater meandecrease from baseline in Patient's Assessment of Total Back Pain atweek 14 than those on placebo (−3.00 versus −1.47). Additionally,patients in the treatment group experienced significantly greaterimprovement in physical function as assessed by mean change frombaseline in Bath Ankylosing Spondylitis Functional Index (BASFI)compared to patients on placebo (−2.26 versus −1.09). All rankedsecondary endpoints achieved p-values of <0.0001 versus placebo.Additional results are summarized below in Table 201.

TABLE 20I SELECT-AXIS 2 (Study 1) Efficacy Results at Week 14*^(,1)RINVOQ 15 mg, once daily Placebo (n = 211) (n = 209) Percent of Patientsachieving ASAS40^(a) 45% 18% Percent of Patients achieving ASDAS Low 44%10% Disease Activity^(b) Mean Change from Baseline in Magnetic −3.95−0.04 Resonance Imaging (MRI) SPARCC Score (Spine)^(c) Mean Change fromBaseline in Patient's −3.00 −1.47 Assessment of Total Back Pain^(d) MeanChange from Baseline in BASFI^(e) −2.26 −1.09 *Primary and rankedsecondary endpoints at Week 14. Not all ranked secondary endpoints areshown. All primary and ranked secondary endpoints achieved p-values of<0.0001 versus placebo. ^(a)ASAS 40 is defined as a ≥40 percentimprovement and an absolute improvement of ≥2 units (on a scale of 0 to10) from Baseline in at least 3 of the 4 domains (patient's globalassessment, back pain, function, and inflammation) with no worsening atall in the remaining domain. ^(b)ASDAS Low Disease Activity is definedas ASDAS score <2.1. ^(c)SPARCC scores for spine are calculated byadding up the dichotomous outcomes from evaluations of the presence,depth, and intensity of bone marrow edema lesions of the spine. ^(d)BackPain is measured using 0-10 numerical rating scale (NRS) for Total BackPain (0 = no pain and 10 = severe pain). ^(e)BASFI is a validatedpatient-reported outcome (PRO) instrument for use in the AS patientpopulation. It consists of 10 items measured on a 0 to 10 NRS, whichassesses the ability to perform activities known to be problematic to ASpatients such as dressing, bending, reaching, turning, and climbingsteps. The total scores range from 0 to 10.

The observed treatment effects comparing bDMARD-naïve population tobDMARD-IR (Study 1) are also provided in FIG. 12 .

Example 33. A Phase 3 Randomized, Placebo-Controlled, Double-BlindProgram to Evaluate Efficacy and Safety of Upadacitinib in AdultSubjects with Axial Spondyloarthritis Followed by a Remission-WithdrawalPeriod (SELECT AXIS 2) (Study 2)

The Phase 3 clinical study plan is set forth in FIG. 9 .

Adult Subjects with Active Non-Radiographic Axial Spondyloarthritis(Nr-axSpA) (Study 2)

Study 2 is a Phase 3, randomized, placebo-controlled, double-blindmulticenter study to evaluate the safety, tolerability, and efficacy ofupadacitinib compared with placebo on reduction of signs and symptoms inadult subjects with active non-radiographic axial spondyloarthritis(nr-axSpA).

Study 2 (nr-axSpA) is comprised of a 35-day Screening Period; a 52-weekrandomized, double-blind, parallel-group, placebo-controlled period (theDouble-Blind Period) designed to compare the safety and efficacy ofupadacitinib freebase 15 mg QD versus placebo for the treatment of signsand symptoms of subjects with active nr-axSpA; and a 52-week open-label,long-term extension period (the Open-Label Extension Period) forevaluating the long-term safety, tolerability, and efficacy ofupadacitinib freebase 15 mg QD in subjects who have completed the DoubleBlind Period up to week 104 (FIG. 9 ). The study team will be unblindedto perform the Week 14 primary analysis. Sites and subjects will remainblinded to the Double-Blind Period treatment assignments for theduration of the study.

Subjects in Study 2 who reach Week 104 on study drug (upadacitinib freebase 15 mg QD) will be assessed whether they are in remission. Subjectsin remission at Week 104 will be eligible for the Remission-WithdrawalPeriod. Subjects will be followed without study drug treatment andassessed for disease flare through Week 152. Subjects who flare willreceive open-label upadacitinib 15 mg QD from the time of flare for 24weeks (re-treatment) or longer.

Subjects in the placebo group will be switched to upadacitinib free base15 mg QD at Week 52 in the Open-Label Extension Period for Study 2(nr-axSpA).

Subjects were randomized in a 1:1 ratio to one of two treatment groups,stratified by MRI and screening hsCRP status (MRI+/hsCRP>ULN,MRI+hsCRP≤ULN, and MRI−/hsCRP>ULN), and exposure to bDMARDs (yes vs no):

-   -   Group 1: Upadacitinib free base 15 mg QD (N=156) (Double-Blind        Period)→Upadacitinib free base 15 mg QD (Open-Label Period)    -   Group 2: Placebo (N=158) (Double-Blind Period)→Upadacitinib free        base 15 mg QD (Open-Label Period)

Subjects were enrolled from 113 sites in 23 countries. Eligible subjectswere adult females and males who were at least 18 years of age atScreening with a clinical diagnosis of nr-axSpA fulfilling the 2009 ASASclassification criteria for axSpA but not meeting the radiologiccriterion of the modified New York criteria for AS and have objectivesigns of active inflammation on magnetic resonance imaging of sacroiliacjoints or based on high sensitivity C-reactive protein >upper limit ofnormal (Study 2, nr-axSpA). Eligible study subjects must have had a BathAnkylosing Spondylitis Disease Activity Index score ≥4 and a Patient'sAssessment of Total Back Pain score (Total Back Pain score) ≥4 based ona 0-10 numerical rating scale at the Screening and Baseline Visits.Subject must have had objective signs of active inflammation on MRI ofSI joints or hsCRP>ULN at screening.

For Study 2, subjects with prior failure of nonsteroidalanti-inflammatory drugs (NSAIDs) were enrolled, and prior treatment withat most 1 bDMARD (either 1 TNF inhibitor or 1 IL-17 inhibitor) wasallowed in a subset of subjects (at least 25%, but not exceeding 35% oftotal enrolled subjects). Subjects with prior exposure to 1 bDMARD(either 1 tumor necrosis factor [TNF] inhibitor or 1 interleukin [IL]-17inhibitor) may be enrolled, and the subject must have discontinued thebDMARD due to either intolerance or lack of efficacy. Prior exposure toa 2nd bDMARD was allowed for no more than 30% of subjects if the reasonfor discontinuation was not due to lack of efficacy. Subjects who havehad lack of efficacy to both a TNF inhibitor and IL-17 inhibitor werenot eligible.

Study 2 Primary Endpoints

The primary endpoint is the proportion of subjects achieving an ASAS40response at Week 14.

Secondary endpoints for Study 2 are described below.

Study 2: Nr-axSpA-Specific Criteria

1. Subject must have a clinical diagnosis of nr-axSpA fulfilling the2009 ASAS classification criteria for axSpA but not meeting theradiologic criterion of the modified New York criteria for AS.

2. Subjects with or without prior exposure to a bDMARD may be enrolled.For the subset of subjects with prior bDMARD exposure (at least 25%, butnot exceeding 35% of total enrolled subjects), prior treatment with atmost 1 bDMARD (either 1 TNF inhibitor or 1 IL-17 inhibitor) is allowed,and the subject must have discontinued the bDMARD due to eitherintolerance or lack of efficacy. Subjects who have had lack of efficacyto both a TNF inhibitor and IL-17 inhibitor were not eligible.3. Subject must have objective signs of active inflammation on MRI of SIjoints or hsCRP>ULN at screening.Study 2 Eligibility Criteria:1. Subject must be an adult male or female, at least 18 years of age atScreening.2. Subject must meet the following scores at Screening and BaselineVisits: BASDAI score ≥4 and Total Back Pain score ≥4 based on a 0-10NRS.3. Subject has had an inadequate response to at least 2 NSAIDs over anat least 4-week period in total at maximum recommended or tolerateddoses, or subject has an intolerance to or contraindication for NSAIDs.4. The washout period for bDMARDs prior to the first dose of study drugis specified below:

-   -   ≥4 weeks for etanercept;    -   ≥8 weeks for adalimumab, infliximab, certolizumab, golimumab,        abatacept, tocilizumab, and ixekizumab;    -   ≥12 weeks for ustekinumab;    -   ≥16 weeks for secukinumab;    -   ≥1 year for rituximab OR ≥6 months if B cells have returned to        pre-treatment level or normal reference range (central lab) if        pre-treatment levels are not available;    -   ≥12 weeks or at least 5 times the mean terminal elimination        half-life, whichever is longer, for other bDMARDs.        5. If entering the study on the following concomitant csDMARDs        (MTX (≤25 mg/week); or Sulfasalazine (SSZ) 3 g/day); or        Hydroxychloroquine (≤400 mg/day); or Chloroquine (≤400 mg/day);        or Leflunomide 20 mg/day); or Apremilast 60 mg/day)), subject        must be on a stable dose as indicated below for at least 28 days        prior to the Baseline Visit. A combination of up to 2 background        csDMARDs is allowed EXCEPT the combination of methotrexate (MTX)        and leflunomide.        6. If entering the study on concomitant oral corticosteroids,        subject must be on a stable dose of prednisone (≤10 mg/day) or        oral corticosteroid equivalent for at least 14 days prior to the        Baseline Visit.        7. If entering the study on concomitant NSAIDs, tramadol,        combination of acetaminophen/paracetamol and codeine or        combination of acetaminophen/paracetamol and hydrocodone, and/or        non-opioid analgesics, subject must be on stable dose(s) for at        least 14 days prior to the Baseline Visit.        8. Subject must not have been exposed to any JAK inhibitor.        9. Subject must not have used the following prohibited        concomitant treatments within the specified timeframe prior to        Baseline Visit:    -   Intra-articular joint injections, spinal/paraspinal        injection(s), or parenteral administration of corticosteroids        within 28 days prior to the Baseline Visit. Inhaled or topical        corticosteroids are allowed;    -   Any other csDMARDs (other than those allowed per eligibility        criterion), including thalidomide, within 28 days or 5        half-lives (whichever is longer) of the drug prior to the        Baseline Visit;    -   Opioid analgesics (except for combination of        acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone which are allowed)        within 14 days prior to the Baseline Visit.        10. Subject must not have received a live vaccine within 28 days        (or longer if required locally) prior to the first dose of study        drug or have expected need of live vaccination during study        participation including at least 30 days (or longer if required        locally) after the last dose of study drug.        11. Subject must have no systemic use of known strong cytochrome        P450 3A (CYP3A) inhibitors from Screening through the end of        study drug administration or strong CYP3A inducers 30 days prior        to study drug administration through the end of study drug        administration. Subjects must not use herbal therapies or other        traditional medicines with unknown effects on CYP3A from        Screening through the end of study drug administration.        12. Subject must not have been treated with any investigational        drug of chemical or biologic nature within a minimum of 30 days        or 5 half-lives of the drug (whichever is longer) prior to the        first dose of study drug or is currently enrolled in another        interventional study.        13. Subject must not have a history of an allergic reaction or        significant sensitivity to constituents of the study drug (and        its excipients) and/or other products in the same class.        Study 2 Secondary Endpoints

The key multiplicity-controlled secondary endpoints at Week 14 were asfollows:

TABLE 21A Key multiplicity-controlled secondary endpoints at Week 14(Study 2) 1 Change from Baseline in Ankylosing Spondylitis DiseaseActivity Score (ASDAS) (CRP) 2 Change from Baseline in magneticresonance imaging (MRI) Spondyloarthritis Research Consortium of Canada(SPARCC) score (SI joints) (MRI-Joints SPARCC) 3 BASDAI 50 score 4Proportion of subjects with ASDAS (CRP) Inactive Disease (ASDAS score<1.3) 5 Change from Baseline in Total Back Pain 6 Change from Baselinein Nocturnal Back Pain 7 Proportion of subjects with ASDAS (CRP) LowDisease (ASDAS score <2.1) 8 Proportion of subjects with ASAS partialremission (PR) (an absolute score of ≤2 units for each of the 4 domainsidentified in ASAS40) 9 Change from Baseline in Bath AnkylosingSpondylitis Functional Index (BASFI) (Function) 10 Change from Baselinein Ankylosing Spondylitis Quality of Life (ASQoL) 11 Change fromBaseline in ASAS Health Index (HI) 12 Proportion of subjects with ASAS20response 13 Change from Baseline in Linear Bath Ankylosing SpondylitisMetrology Index (BASMI_(lin)) (Mobility) 14 Change from Baseline inMaastricht Ankylosing Spondylitis Enthesitis Score (MASES) (Enthesitis)

Additional key secondary endpoints at Week 14 include: Change fromBaseline in MRI SPARCC score (spine) at Week 14.

Additional Study 2 Endpoints

Additional endpoints are the following measurements assessed at timepoints other than those specified for the primary and key secondaryvariables are as follows:

TABLE 21B Additional Study 2 Endpoints 1 Proportion of subjects withASAS20 response 2 Proportion of subjects with ASAS40 response 3Proportion of subjects with ASAS PR 4 Proportion of subjects with ASDASInactive Disease (ASDAS score <1.3) 5 Proportion of subjects with ASDASLow Disease (ASDAS score <2.1) 6 Proportion of subjects with ASDAS MajorImprovement (a change from Baseline of ≤−2.0) 7 Proportion of subjectswith ASDAS Clinically Important Improvement (a change from Baseline of≤−1.1) 8 Proportion of subjects with Discontinuation of opioids amongsubjects with opioid use at Baseline 9 Change from Baseline in ASAS HI10 Change from Baseline in ASDAS 11 Change from Baseline in ASQoL 12Change from Baseline in BASDAI and BASDAI Questions including mean ofquestion 5 and 6 of the BASDAI 13 Change from Baseline in BASFI 14Change from Baseline in BASMI_(lin) 15 Change from Baseline in hsCRP 16Change from Baseline in FACIT-F 17 Change from Baseline in EQ-5D-5L 18Change from Baseline in MASES 19 Change from Baseline in mSASSS withconventional radiograph 20 Change from Baseline in MRI SPARCC score ofSI joints 21 Change from Baseline in MRI SPARCC score of spine 22 Changefrom Baseline in Total Back Pain 23 Change from Baseline in NocturnalBack Pain 24 Change from Baseline in Pain 25 Change from Baseline in PGA26 Change from Baseline in PtGA 27 Change from Baseline in SF-36 28Change from Baseline in TJC and SJC 29 Change from Baseline in WPAI 30Change from Baseline in Change of NSAID score

A total of 314 subjects were randomized in Study 2 and 313 receiveddouble blind study drug treatment, out of which 295 (94.2%) completedstudy drug through Week 14. One subject randomized to the placebo groupdid not receive study drug. The rates of premature discontinuation ofstudy drug through Week 14 were 4.5% and 7.1% in the placebo group andthe upadacitinib treatment group respectively (Table 21C). The keydemographics and baseline characteristics were balanced across thetreatment groups and generally consistent with the targeted patientpopulation (Table 21D).

TABLE 21C Subject Disposition UPADACITINIB Subject Disposition PLACEBO15 MG QD Randomized 158 156 Full Analysis Set (FAS)   157^(c) 156 PerProtocol Analysis Set 133 135 Safety Analysis Set 157 156 CompletedStudy Drug 150 (95.5) 145 (92.9) Through Week 14, n(%)^(b) PrematurelyDiscontinued 7 (4.5) 11 (7.1) Study Drug by Week 14^(a), n(%)^(b)Adverse Events 2 (1.3) 4 (2.6) Withdrew Consent 1 (0.6) 2 (1.3) Lost ToFollow-Up  0 0 Lack of Efficacy 3 (1.9) 3 (1.9) COVID-19 Infection  0 0COVID-19 Logistical  0 1 (0.6) Restrictions Other 1 (0.6) 1 (0.6)^(a)Primary reasons for premature discontinuation of study drug aresummarized. ^(b)Percentage is calculated based upon the FAS. ^(c)Onesubject did not receive study drug (decided not to participate afterrandomization).

TABLE 21D Key Demographics and Baseline Characteristics Key Demographicand Baseline UPADACITINIB Characteristics PLACEBO 15 MG QD Mean (SD) orn (%) N = 157 N = 156 Male 63 (40.1) 67 (42.9) Age (Yrs) 42.5 (12.44)41.6 (12.00) HLA-B27 Positive 93 (59.6) 90 (58.8) White 127 (80.9) 134(85.9) Region North America 19 (12.1) 26 (16.7) South/Central America 13(8.3) 12 (7.7) Western Europe 19 (12.1) 24 (15.4) Eastern Europe 72(45.9) 68 (43.6) Asia^(a) 27 (17.2) 19 (12.2) Other^(b) 7 (4.5) 7 (4.5)Duration of nr-axSpA Diagnosis 4.4 (5.83) 4.5 (5.54) (Yrs) Duration ofnr-axSpA Symptom 9.2 (8.12) 9.0 (7.86) (Yrs) NSAIDs Use at Baseline 113(72.0) 121 (77.6) Oral Corticosteroids Use at 17 (10.8) 18 (11.5)Baseline csDMARDs Use at Baseline 50 (31.8) 41 (26.3) Prior bDMARDExposure 54 (34.4) 49 (31.4) BASDAI (0-10) 6.91 (1.215) 6.82 (1.295)Total Back Pain (NRS 0-10) 7.3 (1.39) 7.2 (1.55) Nocturnal Back Pain(NRS 0-10) 7.0 (1.64) 6.7 (1.94) Patient Global Assessment of 7.3 (1.38)7.0 (1.62) Disease Activity (NRS 0-10) ASDAS(CRP) 3.65 (0.644) 3.61(0.674) BASFI (Function) (0-10) 5.99 (2.139) 5.89 (2.077) BASMI(Mobility) 3.10 (1.269) 2.98 (1.418) Presence of Enthesitis 125 (79.6)125 (80.1) (MASES > 0) MASES Score^(c)(0-13) 4.7 (3.18) 4.7 (3.09) MRISpine SPARCC^(d) (0-108) 1.44 (3.724) 2.72 (6.881) MRI Sacroiliac JointSPARCC^(d) 3.49 (7.601) 4.38 (8.737) (0-72) MRI (SI joints) inflammation66 (42.0) 70 (44.9) positive at screening hsCRP at Screening (mg/L)10.52 (13.522) 13.61 24.794) hsCRP > ULN (2.87 mg/L) at 126 (80.3) 123(78.8) Screening hsCRP > 5 mg/L at Screening 84 (53.5) 99 (63.5) MRI (SIjoints) inflammation and hsCRP level at Screening MRI+/hsCRP > ULN 35(22.3) 38 (24.4) MRI+/hsCRP ≤ ULN 31 (19.7) 32 (20.5) MRI−/hsCRP > ULN91 (58.0) 86 (55.1) AS QoL(0-18) 11.9 (4.53) 11.9 (4.41) ASAS HealthIndex (0-17) 9.52 (3.662) 9.44 (3.575) ^(a)China, Taiwan, South Koreaand Japan. ^(b)Australia and Israel. ^(c)Summarized for subjects withpresence of enthesitis at baseline. ^(d)Summarized for subjects withavailable baseline MRI data up to 3 days post first dose of study drug.Efficacy

The primary endpoint was the achievement of an ASAS40 response at Week14. The primary analysis, using Non-Responder Imputation in conjunctionwith Multiple Imputation (NRI-MI) to handle missing data due toCOVID-19, showed a statistically significantly higher response rate(p<0.0001) in the upadacitinib group (44.9%) as compared to placebo(22.5%) (FIG. 13A). Sensitivity and supplementary analyses using NRI, AsObserved (AO) data, and analyses on the Per Protocol population showedconsistent results.

The first 12 of the 14 ranked endpoints at Week 14 were statisticallysignificant. Details of the primary and ranked secondary endpoints arepresented in Table 21E and FIGS. 14A-14F. FIG. 13B shows ASAS40responses up to Week 14. Upadacitinib showed onset of effect in ASAS40as early as Week 2.

TABLE 21E Primary and Ranked Key Secondary Efficacy Endpoints at Week14^(a) UPADACITINIB PLACEBO 15 MG QD UPA − PBO Endpoint N = 157 N = 156(95% CI) p-VALUE^(b) Primary ASAS40 22.5% 44.9% 22.2 (12.1, 32.3)<0.0001* Ranked Key 1 ASDAS(CRP) −0.71 −1.36 −0.65 (−0.85, −0.45)<0.0001* Secondary 2 MRI SI Joints 0.57 −2.49 −3.06 (−4.08, −2.04)<0.0001* SPARCC^(c) 3 BASDAI50 22.1% 42.3% 20.1 (10.1, 30.1) 0.0001* 4ASDAS(CRP) 5.2% 14.1% 8.8 (2.5, 15.2) 0.0063* Inactive Disease 5 TotalBack Pain −2.00 −2.91 −0.92 (−1.42, −0.41) 0.0004* 6 Nocturnal Back−1.84 −2.96 −1.12 (−1.68, −0.55) 0.0001* Pain 7 ASDAS(CRP) 18.3% 42.3%23.8 (14.2, 33.4) <0.0001* Low Disease Activity 8 ASAS Partial 7.6%18.6% 10.9 (3.6, 18.3) 0.0035* Remission 9 BASFI (Function) −1.47 −2.61−1.14 (−1.60, −0.68) <0.0001* 10 AS QoL −3.15 −5.38 −2.23 (−3.26, −1.21)<0.0001* 11 ASAS Health −1.48 −3.26 −1.78 (−2.56, −1.00) <0.0001* Index12 ASAS20 43.8% 66.7% 22.8 (12.2, 33.4) <0.0001* 13 BASMI (Mobility)−0.19 −0.29 −0.10 (−0.25, 0.05) 0.1781 14 MASES −1.6 −2.3 −0.7 (−1.3,−0.1) 0.0193 (Enthesitis)^(d) ^(a)Results for binary endpoints are basedon NRI-MI analysis. Analyses for all continuous endpoints are for thechange from baseline value. Results for continuous endpoints are basedon MMRM, except for MRI and BASMI which use ANCOVA analysis.^(b)Unadjusted raw p-values are presented. *Denotes multiplicityadjusted statistical significance at the pre-specified two-sided 0.05level. ^(c)Summarized for subjects with available baseline MRI data upto 3 days post first dose of study drug and available week 14 MRI data.^(d)Summarized for subjects with presence of enthesitis at baseline (N =125 in Placebo, N = 124 in UPA).Safety

In this Phase 3 nr-axSpA study, the safety profile of upadacitinib wasconsistent with what is known for upadacitinib and no new risks wereidentified.

Adverse Events

The overview of TEAEs and AESIs up to Week 14 are summarized in Table21F and Table 21G respectively. Through week 14, the most common adverseevents (≥3% of patients) with upadacitinib were headache, COVID-19,nasopharyngitis, and nausea. The proportion of patients with adverseevents leading to discontinuation, serious adverse events and seriousinfections were 2.6 percent/2.6 percent/1.3 percent for upadacitinib and1.3 percent/1.3 percent/0.6 percent for placebo, respectively. Seriousinfections included COVID-19 induced pneumonia and pyelonephritis in twopatients on upadacitinib and hemorrhagic fever with renal syndrome inone patient on placebo. Two patients treated with upadacitinib and onetreated with placebo developed non-serious, mild or moderate herpeszoster limited to one dermatome. One patient treated with placebodeveloped a malignancy (basal cell carcinoma). No adjudicated majoradverse cardiovascular events, venous thromboembolic events or deathswere reported in either group through week 14. In summary:

-   -   The rate of overall AEs was similar between the upadacitinib 15        mg and placebo groups. Serious AEs were reported more frequently        with upadacitinib 15 mg (2.6%) compared to placebo (1.3%). AEs        leading to discontinuation of study drug were reported more        frequently with upadacitinib 15 mg (2.6%) compared to placebo        (1.3%). No deaths were reported.    -   Serious infections and herpes zoster were reported with        upadacitinib 15 mg (both at a rate of 1.3%). Both herpes zoster        events were nonserious, did not lead to treatment        discontinuation, and involved a single dermatome.    -   One event of basal cell carcinoma was reported in a subject        receiving placebo. No malignancy was reported with upadacitinib        15 mg.    -   All hepatic disorders reported in the upadacitinib group were        mild or moderate transaminase elevations; none were serious or        led to discontinuation of treatment.    -   AEs of anemia and neutropenia were generally mild or moderate,        nonserious, and did not lead to treatment discontinuation. There        were no AEs of lymphopenia reported.    -   There were no events of opportunistic infection, non-melanoma        skin cancer, lymphoma, adjudicated GI perforation, renal        dysfunction, active tuberculosis, adjudicated MACE or VTE        reported.

TABLE 21F Overview of Treatment-Emergent Adverse Events (TEAE) up toWeek 14 Upadacitinib Placebo 15 mg QD (N = 157) (N = 156) n (%) n (%)Adverse event (AE) 72 (45.9) 75 (48.1) AE with reasonable possibility ofbeing 30 (19.1) 29 (18.6) related to study treatment^($) Severe AE 3(1.9) 8 (5.1) Serious AE 2 (1.3) 4 (2.6) AE leading to withdrawal ofstudy treatment 2 (1.3) 4 (2.6) AE leading to death 0 (0.0) 0 (0.0)COVID-19 related AE# 10 (6.4) 8 (5.1) All deaths 0 (0.0) 0 (0.0) ^($)Asassessed by investigator. #As collected in AE eCRF.

TABLE 21G Overview of Treatment-Emergent Adverse Events of SpecialInterest up to Week 14 Upadacitinib Placebo 15 mg QD (N = 157) (N = 156)n (%) n (%) Infection 36 (22.9) 36 (23.1) Serious infection 1 (0.6) 2(1.3) Opportunistic infection excluding tuberculosis 0 (0.0) 0 (0.0) andherpes zoster Herpes zoster 1 (0.6) 2 (1.3) Active tuberculosis 0 (0.0)0 (0.0) Malignancy 1 (0.6) 0 (0.0) Non-melanoma skin cancer (NMSC) 1(0.6) 0 (0.0) Malignancy other than NMSC 0 (0.0) 0 (0.0) Lymphoma 0(0.0) 0 (0.0) Hepatic disorder 5 (3.2) 4 (2.6) Adjudicatedgastrointestinal perforation 0 (0.0) 0 (0.0) Anemia 0 (0.0) 1 (0.6)Neutropenia 0 (0.0) 5 (3.2) Lymphopenia 0 (0.0) 0 (0.0) Renaldysfunction 0 (0.0) 0 (0.0) Adjudicated MACE* 0 (0.0) 0 (0.0)Adjudicated venous thromboembolic events** 0 (0.0) 0 (0.0) *MACE; Majoradverse cardiovascular events, defined as cardiovascular death (includesacute myocardial infarction, sudden cardiac death, heart failure,cardiovascular procedure-related death, death due to cardiovascularhemorrhage, fatal stroke, pulmonary embolism and other cardiovascularcauses), non-fatal myocardial infarction and non-fatal stroke. **VTEinclude deep vein thrombosis (DVT) and pulmonary embolism (PE) (fataland non-fatal).Potentially Clinically Significant Lab Findings

Potentially clinically significant lab abnormalities were reportedinfrequently (Table 21H). There was no Hy's law case in this study up toWeek 14.

TABLE 21H Potentially Clinically Significant Labs up to Week 14 inDouble-Blind Period UPADACITINIB Lab Parameter^(a) PLACEBO 15 MG QDn/N_obs (%) N = 157 N = 156 Hemoglobin (g/L) Grade 3 (<80) 0/156 0/154Lymphocytes (×10{circumflex over ( )}9/L) Grade 3 (0.2-<0.5) 1/156 (0.6)2/154 (1.3) Grade 4 (<0.2) 0/156 0/154 Neutrophils (×10{circumflex over( )}9/L) Grade 3 (0.5-<1.0) 1/156 (0.6) 2/154 (1.3) Grade 4 (<0.5) 0/1560/154 ALT (U/L) Grade 3 (>5.0-20.0 xULN) 0/156 0/154 Grade 4 (>20.0xULN) 0/156 0/154 AST (U/L) Grade 3 (>5.0-20.0 xULN) 0/156 0/154 Grade 4(>20.0 xULN) 0/156 0/154 Creatinine (umol/L) Grade 3 (>3.0-6.0 xULN)0/156 0/154 Grade 4 (>6.0 xULN) 0/156 0/154 ^(a)Grading is based CTCAEV4 criteria; Grade must be worse than the baseline grade to be countedPotential Impact of the Study

Overall, the topline results from Study 2 support planned regulatorysubmissions for the nr-axSpA indication.

Upadacitinib demonstrated significantly greater improvements (e.g.,reductions) in nr-axSpA signs and symptoms, including back pain andinflammation, as well as improvements in physical function, diseaseacrivity, and quality of life compared with placebo at Week 14.Significantly more patients treated with upadacitinib achievedAnkylosing Spondylitis Disease Activity Score (ASDAS) Low DiseaseActivity compared to those treated with placebo (42 percent versus 18percent; p<0.0001). A statistically significantly greater improvement inMagnetic Resonance Imaging (MRI) Spondyloarthritis Research Consortiumof Canada (SPARCC) Score (SI Joints) as measured by mean change frombaseline was reported in the upadacitinib group versus the placebo group(−2.49 versus 0.57; p<0.0001). Patients on upadacitinib experiencedsignificantly greater decrease from baseline in Patient's Assessment ofTotal Back Pain at week 14 than those on placebo (−2.91 versus −2.00;p=0.0004). Additionally, patients treated with upadacitinib experiencedsignificantly greater improvement in physical function as assessed bymean change from baseline in Bath Ankylosing Spondylitis FunctionalIndex (BASFI) compared to patients on placebo (−2.61 versus −1.47;p<0.0001). Additional results are summarized in Table 21I below.

TABLE 21I SELECT-AXIS 2 (Study 2) Efficacy Results at Week 14*^(,1)Upadacitinib 15 mg, once daily Placebo (n = 156) (n = 157) Percent ofPatients achieving ASAS40^(a) 45% 23% Percent of Patients achievingASDAS Low 42% 18% Disease Activity^(b) Mean Change from Baseline inMagnetic −2.49 0.57 Resonance Imaging (MRI) SPARCC Score (SI Joints)^(c)Mean Change from Baseline in Patient's −2.91 −2.00 Assessment of TotalBack Pain^(d) Mean Change from Baseline in BASFI^(e) −2.61 −1.47*Primary and ranked secondary endpoints at Week 14. Not all rankedsecondary endpoints are shown. All endpoints shown with the exception oftotal back pain (p = 0.0004) achieved p-values of <0.0001 versusplacebo. ^(a)ASAS 40 is defined as a ≥40 percent improvement and anabsolute improvement of ≥2 units (on a scale of 0 to 10) from Baselinein at least 3 of the 4 domains (patient's global assessment, back pain,function and inflammation) with no worsening at all in the remainingdomain. ^(b)ASDAS Low Disease Activity is defined as ASDAS score <2.1.^(c)SPARCC scores for SI-Joints are calculated by adding up thedichotomous outcomes from evaluations of the presence, depth, andintensity of bone marrow edema lesions of the SI-joints. ^(d)BackPain ismeasured using 0-10 numerical rating scale (NRS) for Total Back Pain (0= no pain and 10 = severe pain). ^(e)BASFI is a validatedpatient-reported outcome (PRO) instrument for use in the axial SpApatient population. It consists of 10 items measured on a 0 to 10 NRS,which assesses the ability to perform activities known to be problematicto axial SpA patients such as dressing, bending, reaching, turning, andclimbing steps. The total scores range from 0 to 10.

U.S. Patent Application Publication Nos. 2017/0129902 and 2021/0228575are incorporated by reference in their entirety and for all purposes.

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

The foregoing has been described of certain non-limiting embodiments ofthe present disclosure. Those of ordinary skill in the art willappreciate that various changes and modifications to this descriptionmay be made without departing from the spirit or scope of the presentdisclosure, as defined in the following claims.

What is claimed is:
 1. A method of treating a human patient havingactive ankylosing spondylitis, comprising orally administering oncedaily to the patient a solid dosage form comprising(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) in an amount sufficient to deliver to the patient 15 mg ofCompound 1 free base equivalent.
 2. The method of claim 1, wherein thepatient is an adult patient.
 3. The method of claim 1, wherein thepatient has had an inadequate response or intolerance to one or moredisease-modifying antirheumatic drugs.
 4. The method of claim 1, whereinthe patient has had an inadequate response or intolerance to one or morenon-steroidal anti-inflammatory drugs (NSAIDs).
 5. The method of claim1, wherein the patient has had an inadequate response or intolerance toan anti-TNF biologic agent.
 6. A method of treating a human patienthaving active ankylosing spondylitis, comprising orally administeringonce daily to the patient a solid dosage form comprising(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) in an amount sufficient to deliver to the patient 15 mg ofCompound 1 free base equivalent, wherein the method results in anAssessment of SpondyloArthritis International Society 40 (ASAS40)response at 14 weeks after the first daily administration.
 7. The methodof claim 6, wherein the patient is an adult patient.
 8. The method ofclaim 6, wherein the patient has had an inadequate response orintolerance to one or more disease-modifying antirheumatic drugs.
 9. Themethod of claim 6, wherein the patient has had an inadequate response orintolerance to one or more non-steroidal anti-inflammatory drugs(NSAIDs).
 10. The method of claim 6, wherein the patient has had aninadequate response or intolerance to an anti-TNF biologic agent.